Sie sind auf Seite 1von 27


Orexin Receptor Antagonists: New Therapeutic Agents for the

Treatment of Insomnia
Anthony J. Roecker,*,† Christopher D. Cox,† and Paul J. Coleman†

Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, 770 Sumneytown Pike, WP14-2, West Point,
Pennsylvania 19486, United States

ABSTRACT: Since its discovery in 1998, the orexin system, composed

of two G-protein coupled receptors, orexins 1 and 2, and two
neuropeptide agonists, orexins A and B, has captured the attention of
See for options on how to legitimately share published articles.

the scientific community as a potential therapeutic target for the

treatment of obesity, anxiety, and sleep/wake disorders. Genetic
Downloaded via UNIV DE BARCELONA on October 11, 2018 at 17:26:37 (UTC).

evidence in rodents, dogs, and humans was revealed between 1999

and 2000, demonstrating a causal link between dysfunction or deletion of
the orexin system and narcolepsy, a disorder characterized by
hypersomnolence during normal wakefulness. These findings encour-
aged efforts to discover agonists to treat narcolepsy and, alternatively,
antagonists to treat insomnia. This perspective will focus on the
discovery and development of structurally diverse orexin antagonists
suitable for preclinical pharmacology studies and human clinical trials.
The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist
for the treatment of insomnia.

It is estimated that 50% of adults in the United States
contact with health care providers to assess the underlying
cause of the patient’s condition followed by the employment of
(approximately 120 million people as per the 2010 census) are behavioral restructuring.5 Concomitant with this effort, several
dissatisfied with their sleep at least a few nights per week.1 options are often pursued including sleep restriction, sleep
While only 3−10% of patients meet the DSM-APA guidelines hygiene modifications, and stimulus control which often afford
for primary insomnia diagnosis, sleep problems are clearly one beneficial effects on sleep profiles for patients. One drawback to
of the most prevalent complaints encountered in clinical this therapy is the recommendation that the patient remain on
practice.2 Insomnia is defined as difficulty initiating or CBT for weeks to months to provide sustained benefit. This
sustaining sleep or finding sleep nonrestorative, and this necessitates higher levels of patient compliance and physician
disorder can present in the absence of another disorder contact compared to pharmacotherapies.
(primary insomnia) or concomitant with a medical condition, When pharmacological treatments are employed, non-
substance abuse problems, or other causative stimuli. The cause benzodiazepine GABAA receptor modulators such as zolpidem
notwithstanding, insomnia has a very high societal cost due to and eszopiclone are considered standard-of-care medications
lost work time as well as increases in injury and comorbid for the treatment of insomnia.6 These drugs exert their effects
disease risk. A study performed in the United States in the mid- through potentiation of the major inhibitory neurotransmitter
1990s estimated the direct cost of absenteeism and lost gamma-aminobutyric acid (GABA), which results in general
productivity to be approximately $40 billion annually, while central nervous system (CNS) depression to facilitate sleep.7,8
indirect costs due to increased accident rates and related These drugs are effective in the initiation of sleep, however,
diseases raised the total to the range of $92−107 billion.3 A sleep maintenance has been an issue for this class of medication
more recent study performed in Quebec in 2009 supported due to short duration of action. This issue has since been
these findings, with the combination of absenteeism, addressed through the advent of controlled release formulations
productivity loss, and increase in accident and disease rates and additional drugs in this class; however, the nature of the
costing the province approximately $5 billion per year.4 With general CNS depression has caused safety concerns for
this cost and patient health in mind, safe and effective options patients.9 Adverse event reports have demonstrated an increase
for the treatment of insomnia represent an area of significant in nighttime parasomnias (sleepwalking,10 eating11) as well as
unmet medical need. an increase in driving accidents related to next-day
While diagnosis of sleep disorders is somewhat complex due somnolence.12,13 These reports have necessitated modified
to difficulties identifying the issues underlying the condition, labeling for GABA modulators,14 and the US FDA required
treatment regimens can be equally complex. Some clinicians
prefer nonpharmaceutical intervention in the form of cognitive- Received: May 30, 2015
behavioral therapy (CBT). This treatment involves increased Published: August 28, 2015

© 2015 American Chemical Society 504 DOI: 10.1021/acs.jmedchem.5b00832

J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

dose lowering for all sedative hypnotic drugs in 2013 due to the a prepro-peptide that produced two peptides with significant
impact of next-day somnolence on traffic accidents.15 Finally, sequence homology to the secretin family of proteins.18
tolerance effects and rebound insomnia have been noted with Because of their localization pattern in the hypothalamus and
zolpidem treatment, which has resulted in the recommendation homology to the secretins, this group named the two peptides
of intermittent use for short periods of time for insomnia hypocretin-1 and hypocretin-2. The team also demonstrated
patients.8 The aforementioned treatment options can be excitatory responses for hypocretin-2 in cultured hypothalamic
effective but have their limitations. The advent of novel neurons, which suggested that these peptides might act as
pharmacotherapies for the treatment of insomnia without the neurotransmitters. It was also suggested by this research team
limitations of current agents would be a welcome advance for that these peptides might act as central regulators of feeding
the millions of patients struggling with insomnia. behavior and energy expenditure. Although both orexin and


hypocretin nomenclature are utilized in the current literature,
this review will use the orexin convention for the remainder of
this perspective.19
The opportunity to view sleep-related disorders from an The discovery of the orexin system and its potential
alternative perspective presented itself in the scientific literature involvement in feeding behavior and energy expenditure
in 1998, although perhaps this was not apparent at the time of inspired significant levels of activity within academic and
initial discovery. In a publication from that year, Sakurai et al. industrial scientific communities. Just one year after the initial
discovered two novel peptides that interacted with an orphan discovery of the orexin system, Lin et al. demonstrated a clear
GPCR (expressed in HEK293 cells) from extracts of rat brain link between OX2R dysfunction and inheritable canine
homogenates.16 When purified to homogeneity, these two narcolepsy in a landmark publication.20 The team demon-
peptides were found to increase intracellular calcium ion strated that narcoleptic canine subjects had mutations in the
concentrations (Ca2+) consistent with GPCR activation. gene that encodes for OX2R which ultimately caused the
Further work identified the amino acid sequence of both disorder. This report established the link between the orexin
peptides, the prepro-orexin peptide from which these two system and the sleep/wake cycle, suggesting that ligands that
peptides are derived, the identity of a second GPCR closely perturb the orexin system might be useful for the treatment of
related to the first receptor, and potency values in a radioligand sleep disorders. These findings might be considered a change in
displacement assay for the peptides against their targets. From mindset about the origins of insomnia; a shift from the thought
these initial studies, this group of scientists named the peptides that insomnia was a sleep disorder to the perspective that
orexin A (OX-A) and orexin B (OX-B) and their target insomnia might be a disease of inappropriate wakefulness.2 The
receptors orexin-1 (OX1R) and orexin-2 (OX2R, see Figure 1). description of the genetic etiology of canine narcolepsy was
quickly followed in nearly concomitant fashion via a publication
from Chemelli et al. that demonstrated orexin knockout mice
displayed evidence of narcolepsy, characterized by the
interruption of normal wakefulness by intermittent bouts of
REM sleep, via electroencephalography (EEG) when compared
to wild-type animals.21
Finally, a link was established in 2000 between human
narcolepsy and the orexin system in two separate clinical
studies. Thannickal et al. utilized tissues from donors to
establish that human subjects suffering from narcolepsy
demonstrated diminished numbers of hypothalamic orexin
neurons compared to non-narcoleptic patients via immunos-
taining protocols.22 In a second study, Nishino et al. evaluated
orexin-A concentrations from cerebrospinal fluid (CSF) of nine
patients with narcolepsy as well as eight control subjects.23
Seven out of nine patients suffering from narcolepsy showed no
detectable orexin-A peptide in CSF samples, while all control
subjects displayed similar CSF concentrations of orexin-A.
Together with rapidly accumulating evidence from numerous
Figure 1. Production of orexin-A (OX-A) and orexin-B (OX-B) from laboratories, these studies helped to define the role of orexins in
the HCRT gene and prepro-orexin peptide and radioligand binding sleep/wake signaling (Figure 2).
potency values against OX1R and OX2R.
The level of genetic validation of the orexin system from
mice to dogs to humans for the potential treatment of sleep
The genesis of this naming convention arose from the Greek disorders quickly caught the attention of the pharmaceutical
work “orexis” meaning appetite, due to the ability of OX-A and industry. Shortly after the publications on human narcolepsy in
OX-B to stimulate feeding behavior in rats upon central 2000, the first publications on truncation of orexin peptides24,25
administration. These results, as well as localization of orexin to afford novel agonists as potential treatments for narcolepsy
producing neurons in the hypothalamus, led the team to believe were published as well as the first small molecule receptor
that the orexin neuropeptides were key regulators of feeding antagonists for the treatment of sleep disorders such as
behavior and perhaps a novel target for pharmaceutical insomnia. For the purposes of this perspective, we will focus on
intervention.17 the discovery and development of orexin antagonists for
Parallel to the efforts described above, de Lecea and Kilduff insomnia treatment. For readers interested in detailed reviews
et al. discovered a specific hypothalamic mRNA which encoded of orexin biology, several high quality reviews covering all
505 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 2. Orexin projections and OXR expression patterns associated with arousal and reward pathways. NE = noradrenergic; 5-HT = serotonergic;
Ach = cholinergic; DA = dopaminergic; HA = histaminergic; NAc = nucleus accumbens.

Figure 3. Representative 1-SORA, 2-SORA, and DORA ligands discovered from screening efforts between 1998 and 2007.

aspects of orexin biology and pharmacology have been recently activity between 1999 and 2007, with the aim of discovering
published.26−28 novel orexin antagonists. During this period alone, over 50


patent applications were filed from numerous companies
seeking to identify small molecule antagonists to elucidate
receptor pharmacology.29 It should be noted that scientists
The discovery, characterization, and genetic association of the from SmithKline Beecham (now GlaxoSmithKline; referred to
orexin system with the sleep/wake cycle as well as suggestions as GSK hereafter) were coauthors on the primary communi-
of other potential indications inspired a flurry of industry cation of the discovery of the orexin system in 1998. In the
506 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 4. Discovery of DORA 15: the first DORA to reach clinical evaluation for the treatment of insomnia.

early 2000s, several questions were immediately apparent from in either FLIPR or binding, while dual antagonists have <20×
a drug discovery perspective. First, while GPCR targets are selectivity between receptor subtypes.33 Optimization of the
generally thought to be highly attractive drug targets,30 would initial hit afforded the discovery of 1-SORA 1 (SB-334867), a
screening efforts be successful in uncovering orexin antagonist potent, selective, and brain penetrant small molecule. While
leads? Second, what style of orexin antagonist would be the compound 1 lacked oral bioavailability, it demonstrated
most effective for the treatment of insomnia: selective OX1R significant reversal of orexin-A induced grooming behavior
(1-SORA), selective OX2R (2-SORA), or dual orexin receptor without notable sedation in rats upon peripheral admin-
antagonists (DORAs)? Finally, would small molecule antago- istration.34 Compound 1 continues to be an important tool
nists recapitulate the genetic phenotype of reduced wakeful- compound in the orexin field, as it has been utilized in over 200
ness, and would this translate into an effective insomnia publications to date exploring orexin pharmacology.35,36 The
treatment? The remainder of this article will seek to provide GSK group followed the discovery of 1 with two additional 1-
perspective and potential answers to these questions. SORA ligands, compounds 2 (SB-408124) and 3 (SB-
Figure 3 depicts a selection of small molecule orexin 674042).37 1-SORA 2 is less often used in pharmacology
antagonists of varying selectivity profiles discovered prior to studies than 1 but is still an important ligand due to its
2007. As stated above, GSK demonstrated significant interest in improved oral bioavailability in rats. Tritiation of compound 3
orexin as a target for drug discovery. Indeed, the GSK team afforded the first highly potent radioligand to support an OX1R
published the first paper on orexin antagonists in the primary binding assay. These tools set the stage for additional
literature describing the discovery of a series of 1,3-biaryl ureas discoveries from other research groups.
as 1-SORA lead molecules.31,32 This discovery was made using 2-SORA ligands were discovered shortly after their 1-SORA
a high-throughput screen (HTS) using a fluorescence imaging counterparts by scientists from Johnson & Johnson (J&J),
plate reader (FLIPR) assay in CHO (Chinese hamster ovary) Merck, and Actelion. 2-SORA 4 (JNJ-1037049) bears
cells expressing OX1R and OX2R, measuring inhibition of significant resemblance to 1-SORAs 1 and 2, owning a central
orexin-induced intracellular calcium release. This assay urea motif. However, this ligand was unearthed from an HTS
(potencies expressed as IC50 or pKB values), along with lead of distinct origin.38 This represented an early example of
radioligand binding assays (potencies expressed as Ki values), pharmacology switching in the orexin field between 1- and 2-
are the primary assays utilized in the orexin field and are used to SORAs with a common core. The term pharmacology
express potencies throughout this manuscript. It should be switching in the orexin field is defined in this manuscript as
noted that selective orexin receptor antagonists are defined moving between selectivity profiles (DORA, 1-SORA, and 2-
herein as >20× selective for either OX1R or OX2R as measured SORA) with relatively small changes in overall structure. While
507 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

not a focus of current orexin literature, this intriguing several rounds of parallel synthesis, ultimately discovering that
phenomenon will be covered later in this article (vide infra). transposition of the benzylamide aromatic motif to afford
Compound 4 was highly potent on OX2R, with a pKB of 8.3, phenylglycine THIQ 14 was well tolerated and maintained an
600-fold selectivity over OX1R, and high levels of selectivity excellent DORA profile. While no additional information is
over other targets. After several years, this 2-SORA ligand was available in the primary literature, it is clear that the Actelion
reported to have efficacy in rat sleep experiments as determined team utilized leads such as DORA 14 to further optimize
by electroencephalographic (EEG) measurements upon potency, physicochemical properties, pharmacokinetics, and in
peripheral dosing (IP, intraperitoneal).39 To the best of our vivo efficacy in preclinical sleep models. These efforts were
knowledge, this was the first reported example of in vivo successful in discovering compound 15, a highly potent DORA
efficacy with a 2-SORA ligand. Research groups at Merck and with appropriate properties for additional characterization.
Actelion discovered additional series of 2-SORA ligands such as The Actelion team published a landmark article in 2007 in
tetrahydroisoquinoline 5 and glycine sulfonamide 6 (EMPA), the journal Nature Medicine describing the preclinical and early
respectively, demonstrating significant structural diversity clinical characterization of DORA 15 (ACT-078573; almorex-
within the orexin antagonist field.40,41 The Merck and Actelion ant) in rodent and canine sleep models as well as in healthy
research teams also described several DORA series of interest human subjects.46 This orexin antagonist was one of the most
arising from HTS efforts such as tricyclic quinazolinone 7,42 potent reported at the time, with an OX1R IC50 of 13 nM and
proline bis-amide 8,43 and glycine sulfonamide 9.44 It should be an OX2R IC50 of 8 nM as well as an excellent selectivity profile
noted that DORAs 8 and 9 could be considered excellent over a large panel of GPCR, ion channel, and enzyme targets
examples of pharmacology switching from 1-SORA 3 and 2- (Figure 5). While DORA 15 was highly protein bound in
SORA 6, respectively. DORA 8 was able to demonstrate dose-
dependent efficacy in an orexin-A induced hyperlocomotion
assay when dosed peripherally. Both DORAs 8 and 9 were able
to demonstrate sleep efficacy in rats when dosed orally, albeit at
high doses of 100 and 300 mg/kg, respectively. These
compounds were able to reduce active wake and increase
REM (rapid eye movement) and NREM (nonrapid eye
movement) sleep during the active phase of rats with
comparable efficacy to that found with 2-SORA 4. In total,
the discovery of many chemotypes of varying selectivity profiles
indicated that the orexin system was highly druggable. While
not optimal, the in vivo sleep efficacy demonstrated by 2-
SORAs and DORAs, and the lack of sleep efficacy for 1-SORAs,
suggested these two classes of orexin antagonists held potential
as treatments for insomnia. The development of compounds
with profiles commensurate with clinical evaluation will be
illustrated in the next section commencing with disclosures
from Actelion in 2007.


Actelion Pharmaceuticals, Ltd. was one of the first companies
to demonstrate significant interest in the orexin field, Figure 5. Preclinical characterization of DORA 15.
exemplified by their discovery of antagonists such as 2-SORA
6 and DORAs 7 and 9 (Figure 3). Their HTS efforts also
uncovered a series of tetrahydroisoquinoline (THIQ) antago- rodent, it demonstrated unbound brain concentrations in
nist hits that bear some resemblance to 2-SORA 5 in Figure 3 reasonable proportion to unbound plasma as measured by CSF
from Merck discovered in the same time period. In contrast to concentration, suggesting adequate brain penetration. Most
2-SORA 5, the Actelion lead compound 10 displayed a 1-SORA notably, DORA 15 was moderately bioavailable in rat and dog
profile with 68-fold functional selectivity (FLIPR assay format) which enabled evaluation of sleep efficacy. When DORA 15
over OX2R as shown in Figure 4.45 The modular structure of was administered orally to rats during their active period, dose-
lead compound 10 afforded an opportunity to employ parallel dependent sleep efficacy was observed as measured by EEG and
chemistry efforts to enable facile modification of various regions EMG (electromyogram) recordings showing significantly
of the lead quickly. Modifications of the amide portion of the decreased active wake efficiency (efficiency = normalized to a
molecule afforded large increases in potency on both receptors defined period of time; in this case 12 h) and increases in REM
as demonstrated by methoxyindane amide 11. Small and NREM efficiency (≥30 mg/kg) in proportion to normal
modifications of the dimethoxy-THIQ core structure afforded physiological sleep.47 Table 1 displays the data representing the
significant enhancement of OX1R potency and selectivity as hallmark DORA rat sleep efficacy profile with significant
demonstrated by 12. Taken together, it was readily apparent increases in NREM and REM duration as well diminished time
that small changes in structure could afford large swings in to enter into both stages of sleep. This EEG profile was
selectivity profile. Additional DORA SAR (structure−activity compared to rodent doses of zolpidem (100 mg/kg, Ambien),
relationships) was uncovered through modification of the and marked differences in the proportion of REM efficiency
Southern aromatic ring as replacement of the 3,4-dimethoxy were noted. Zolpidem significantly reduced REM efficiency,
motif with a 3,4-dichloro system (13) afforded a DORA profile. which constituted the first evidence of differentiation between
The Actelion team expanded upon this initial SAR finding with orexin antagonism and GABAA modulation as it pertained to
508 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Table 1. Rat Sleep Characteristics of DORA 15 after Oral

Administration to Male Wistar Rats
sleep parameter 100 mg/kg DORA vehicle P-value Mann−
(12 h night) 15 (PO, n = 15) (n = 15) Whitney test
NREM sleep 286 ± 8 243 ± 8 0.002
duration (min)
REM sleep duration 50 ± 6 33 ± 4 0.02
latency to persistent 30 ± 2 40 ± 3 0.02
NREM (min)
latency to persistent 91 ± 20 101 ± 17 0.39
REM (min)

sleep architecture. In addition to sleep architecture differences,

the pharmacology differences between orexin antagonism and
GABA modulators have been expanded through the efforts of
additional research groups to include wider preclinical
therapeutic margins for orexin antagonists on cognition end
In beagle dogs, active phase administration of DORA 15
demonstrated dose-dependent decreases in mobility scores as
assessed by video monitoring of sleep postures and time spent
in quiet wake states. These effects achieved statistical
significance at 100 mg/kg, and it was noted that entry of a
familiar person during the course of the experiment did not
elicit stimulus-induced cataplexy, which is often observed in
narcoleptic dogs. This was the first published indication that
pharmacological antagonism of the orexin system with small
molecules could reduce wakefulness in nonrodent species. In
healthy male subjects, oral administration of DORA 15 afforded Figure 6. Major metabolites identified after a 200 mg dose of DORA
diminished alertness as assessed by Bond−Ladder visual 15 to human volunteers.
analogue scale (VAS) at doses of greater than or equal to
400 mg. EEG recordings from these patients also indicated the bioavailability of DORA 15 in human subjects was determined
onset of stage 2 (NREM) sleep at doses of 200 mg of DORA to be 11%, likely due to high first pass metabolism. Taken
15. This constellation of studies was the first to demonstrate together, the metabolite profile and oral bioavailability of
translation of preclinical sleep efficacy to human subjects; a DORA 15 provided additional opportunities in the field for
crucial finding for the field. On the basis of this data, DORA 15 compound optimization. Nonetheless, the discovery, preclin-
was advanced into clinical studies for the treatment of ical, and early clinical characterization of DORA 15 represented
insomnia. The clinical trial data for all candidates will be a breakthrough in the orexin field.
compared in an upcoming section. After the discovery of DORA 15, Actelion researchers
While no preclinical drug metabolism data was available for continued the search for additional series of orexin antagonists
DORA 15 at the time of preparation of this manuscript, one to optimize toward clinical candidates. A recent publication
concern from a medicinal chemistry design perspective was the described the identification and development of a structurally
possibility of latent electrophilicity of the dimethoxy-THIQ distinct series of DORAs represented by proline sulfonamide
motif that might arise from metabolism in vivo.49 A recent lead 20 (Figure 7).52 This relatively compact lead structure
publication from the Actelion team describing the metabolism, demonstrated excellent functional potency at both orexin
disposition, and excretion of a radiolabeled form of DORA 15 receptors comparable to DORA 15, adequate brain penetration,
shed some light on this possibility.50 After oral administration but high rat and human microsomal clearance. The presence of
of 200 mg to six healthy male volunteers, DORA 15 was a halogenated thiophene motif and an arylthiomethyl anilide
extensively metabolized, generating 47 unique metabolites in were not optimal regarding potential for bioacitvation and
vivo (21 in plasma), four of which were major components as metabolism, hence the Actelion team took a modular SAR
shown in Figure 6. Of the four major metabolites, approach to optimize DORA 20 focused on replacing those
isoquinolinium 16 could be considered directly electrophilic motifs. Initial screening unearthed a 4-methoxyphenyl sub-
and phenolic metabolites 18 and 19 could generate electro- stituent in DORA 21 as an isostere for the bromothiophene
philic intermediates in the form of ortho-quinones or para- motif. However, this analogue suffered from moderate CYP3A4
quinone methides upon additional oxidation. The absolute inhibitory activity (IC50 = 8 μM). Screening analogues of the
concentration of each of these metabolites was comparable to anilide portion of the molecule afforded a 3,5-dimethylphenyl
parent DORA 15, and this might represent a risk for substructure in DORA 22 as a replacement for the
idiosyncratic toxicity through trapping of biologically relevant arylthiomethyl anilide that maintained orexin potency while
nucleophiles. These clinical metabolic findings might have diminishing CYP3A4 inhibitory activity (IC50 = 15 μM). While
contributed to the discontinuation of clinical development of extensive SAR was explored to further optimize the properties
DORA 15 due to “infrequent transient increases in liver of DORA 22, no modifications were discovered that offered
enzymes” as recently reported.51 Additionally, the oral additional improvement of the CYP3A4 inhibition profile.
509 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

protein bound and retained the CNS penetration of the initial

lead. The excision of the bromothiophene in lead molecule
DORA 20 resulted in improved in vitro (microsomal clearance)
and in vivo pharmacokinetic parameters, although it should be
noted that aniline metabolites can pose a bioactivation risk in
clinical development.53 DORA 22 demonstrated moderate
clearance and oral bioavailability in rat and dog as well as an
acceptable half-life for an agent for the treatment of insomnia
(∼2 h). This optimized DORA was characterized in oral EEG
experiments and afforded significant reductions in active wake
and increases in NREM and REM sleep at 100 mg/kg and 100
mg/day (∼10 mg/kg for a 10 kg dog) in rat and dog,
respectively. On the basis of this characterization, DORA 22
(ACT-462206) was advanced toward clinical evaluation.


GSK was a key player in orexin research from its inception.
While a publication describing the discovery of DORA 28 (SB-
649868) appeared in 2011,54 it was clear from the patent
literature that a portion of this effort may have occurred much
earlier.55 Similar to other companies, GSK screened their small
molecule sample collection searching for attractive medicinal
chemistry starting points. Several compounds with the
piperidine amide structure 23 were found to have functional
antagonist activity on both orexin receptors (Figure 9), and
compound 24 was an example of a high nanomolar antagonist
lead compound. As piperidines are replete in medicinal
chemistry,56 these represented excellent starting points for
chemical exploration. An initial screen of substituted amides
uncovered that the ortho-biaryl motif in 25 imparted significant
potency improvements on both OX1R and OX2R to afford low
nanomolar functional antagonists. It is noteworthy that this
ortho-biaryl/biheterocycle motif discovered in the early 2000s
Figure 7. Discovery of DORA 22: a structurally distinct DORA clinical would become a key SAR element for many future orexin
candidate for insomnia treatment.
medicinal chemistry efforts (vide infra). While very potent,
DORA 25 displayed high clearance in microsomal incubations.
Hence, this molecule was advanced for additional in vivo The GSK team attributed this finding to the highly lipophilic
studies. nature of the lead and/or the lability of the ether motif. In an
DORA 22 demonstrated excellent specificity for orexin effort to replace the ether functionality, the team surveyed
activity with no activities less than 10 μM observed in a broad ketone, urea, and amide linkers and uncovered bis-amide S-26
screening panel of 124 targets (Figure 8). DORA 22 was highly as a subnanomolar antagonist of both orexin receptors with
improved microsomal stability. From lead DORA 26, two
parallel SAR efforts were undertaken to reduce the lipophilicity
imparted by the piperidine biaryl as well as to replace the
eastern aromatic ring (generic structure 27). Broad heterocycle
scanning of both phenyl rings in the piperidine amide
uncovered the 2-aryl-5-methylthiazole motif as the isosteric
replacement with the best balance of orexin potency, selectivity,
and improved physicochemical properties. A second broad
heterocyclic scan replaced the fluorophenyl ring in 26 with a
benzofuran moiety to afford 28, a highly potent DORA with
low microsomal clearance in rat and dog which warranted
additional profiling.
DORA 28 demonstrated subnanomolar potency against both
orexin receptors, excellent levels of selectivity over other
targets, high protein binding in the rat, and moderate brain
penetration (Figure 10). Although the brain-to-blood ratio was
low in this case, the unbound brain (5.3%) to unbound plasma
levels (1.4%) indicate adequate brain penetration. This
compound demonstrated moderate plasma clearance, a short
half-life, and excellent bioavailability in the rat which supported
Figure 8. Preclinical characterization of DORA 22. (a) mL/min/kg. efficacy evaluation. When dosed orally, DORA 28 was able to
510 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 9. Discovery of DORA 28: a highly potent, orally bioavailable DORA clinical candidate.

but greater in magnitude, to those found for DORAs 15 and 22,

likely due to improved potency of this orexin antagonist. At this
stage, DORA 28 was selected for additional characterization in
preparation for clinical studies.
The presence of a 2,3-unsubstituted benzofuran in DORA 28
raised concern for bioactivation in a similar manner to those of
DORA 15 (Figure 5), although through a different mechanistic
pathway. The GSK team published a drug metabolism study in
healthy human subjects in the same year they published the
discovery of DORA 28 which shed some light on this topic.57
This study monitored the metabolic fate of a 30 mg oral dose of
radiolabeled DORA 28 in eight subjects. Surprisingly, the
apparent half-life of radioactivity (39 h) significantly exceeded
the half-life of the parent molecule (5 h), suggesting retention
of long-lived metabolites (Figure 11). The authors reported
that DORA 28 was extensively metabolized in vivo, with two
major metabolites residing in plasma extracts, namely 31 and
32, present in 11% and 2% of the radioactive dose, respectively.
These metabolites suggested that oxidation of the benzofuran
Figure 10. Preclinical characterization of DORA 28. TST = total sleep was a major route of metabolism for DORA 28, and the
time. mechanism of formation of 31 and 32 can be rationalized
through expoxide 29 and aldehyde 30. The presence of epoxide
reverse orexin-A induced grooming behavior in the rat (an 29 was confirmed through glutathione (GSH) trapping
assay similar to orexin-A induced locomotion for DORA 8, experiments, thus demonstrating that biologically relevant
Figure 3) at 3 mg/kg. At slightly higher oral doses of 10 mg/kg, nucleophiles could be efficiently trapped by these intermedi-
DORA 28 was able to significantly increase REM and NREM ates. The authors mentioned literature precedent that
total sleep time (TST) in freely moving telemetrized rats intermediates such as 29 and 30 could increase potential for
during their active phase. These results are similar in direction, idiosyncratic toxicity, however, the low predicted therapeutic
511 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 11. Major metabolites identified after a 30 mg dose of DORA 28 to human volunteers. Structures in brackets are putative metabolic

dose of DORA 28 (∼20 mg) might mitigate these concerns.49 The modular structure of 35 enabled exploration of both
The sleep efficacy of the previous DORAs is impressive, heterocycle and amide SAR via parallel synthesis, and diazepane
although preclinical bioactivation risk for DORAs 15 and 28 36 was discovered to possess an excellent combination of
afforded additional opportunities for DORA series optimiza- functional potency on both receptors and physicochemical
tion.58 properties (cLogP = 3.1 for 36, 4.5 for 35).60 Upon further

exploration, the team found 36 to possess acceptable brain
DORA CLINICAL CANDIDATES FROM MERCK penetration with no P-glycoprotein (Pgp) mediated transport,
excellent cellular permeability, high selectivity for the orexin
A team at Merck began DORA discovery work in early 2005 by receptors (Panlabs screen), and measurable free fraction that
dissecting the orexin literature and executing an HTS utilizing led to significant levels of drug exposure in the CSF. Upon oral
functional FLIPR assays against both OX1R and OX2R. As part dosing at 100 mg/kg, 36 decreased the amount of time rats
of these efforts, the team identified piperidine 33 that had spent in active wake while increasing time in NREM and REM
favorable potency against both receptors but poor physico- sleep. Hence, compound 36 was further profiled as a highly
chemical properties. Modifications of the benzamide, piperidine promising candidate for development, however, poor pharma-
core, and eastern heterocycle afforded compounds such as cokinetics and the bioactivation potential (vide infra) of this
linear diamine 34 that possessed excellent potency, good brain lead limited further advancement of the compound and
penetration, and demonstrated in vivo efficacy in rat sleep prompted the team to further investigate these issues.
studies following peripheral dosing (Figure 12).59 Unfortu- In an effort to better understand the metabolic fate of 36, a
nately, the pharmacokinetic properties of these linear diamines number of studies were carried out including intravenous and
could not be optimized to meet development criteria due to oral pharmacokinetic studies (rat and dog), microsomal
extensive oxidative metabolism, especially on the N-alkyl incubation with metabolite identification (rat, dog, and
substituents. Part of the team’s strategy to mitigate CYP- human both with and without semicarbazide), a bile-duct
mediated metabolism issues focused on the reintroduction of cannulated study with portal/cephalic vein infusion (dog), and
novel cyclic constraints to the linear diamine framework to covalent protein binding studies (rat and human). The team
shield these positions from metabolism with the added garnered several important findings from these studies that
advantage of reducing rotable bonds (see ref 57). More than impacted the lead optimization strategy moving forward: (1)
two dozen different cyclic constraints were investigated, but the dog was a more suitable species for pharmacokinetic
most successful constraint turned out to be the seven- optimization than rat based on similarity to human metabolism;
membered diazepane ring present in compound 35. (2) despite moderate plasma clearance in dog, 36 underwent
512 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 12. Discovery of DORA 39: a potent, orally bioavailable DORA clinical candidate.

significant first-pass metabolism that limited bioavailability; (3) but that some of these conformations resulted in significant
surprisingly high levels of covalent binding were detected, upfield proton resonance shifts most readily explained by
indicating oxidative metabolism of 36 occurred to reveal a intramolecular isotropic shielding. Detailed analysis of 36 and a
reactive metabolite; (4) significant levels of oxidative closely related analogue by multiple NMR techniques revealed
metabolism occurred throughout the molecule including that the lowest energy, and thus most populated conformation,
oxidation of the tolyl methyl group, on the diazepane core, was, surprisingly, one in which the two aromatic moieties
and quinazoline heterocycle; and (5) microsomal incubations existed in a π-stacking arrangement that resulted in an overall
containing semicarbazide trapped intermediates suggesting that horseshoe-, or U-shaped conformation, as pictured in Figure
oxidation of one of the core methylene groups adjacent to a 12. Extensive computational analysis of 36 supported that
nitrogen atom was likely a metabolic pathway. In summary, the observation, and single crystal X-ray analysis revealed that the
team hypothesized that removing the tolyl methyl group, low-energy conformation of 36 in the solid state is also the U-
blocking positions on the core adjacent to nitrogen atoms, and shaped conformation. These observations led the team to
alteration of the heterocycle might improve pharmacokinetics hypothesize that a potential reason the diazepanes exhibited
and reduce bioactivation. favorable potency is that this low energy conformation could be
During initial synthetic exploration of the diazepane series, similar to their binding conformation at the receptor, thus
NMR spectral analysis indicated that these compounds not diazepanes suffer no entropic penalty for adopting a bioactive
only existed in multiple low-energy conformations in solution conformation. To probe this question, the macrocyclic
513 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 13. Structure and binding potency of the acyclic precursor and macrocyclic analogue of 36.

Figure 14. Putative structure and mechanism of covalent adduct formation upon incubation of 38 in the presence of glutathione (GSH).

analogue 41, as well as its acyclic precursor 40, were standard (the GSH/IS ratio; ratio = 3.3 for 38). Careful analysis
synthesized and tested for their ability to bind OX1R and of the HRMS data on 38 revealed that the major GSH adduct
OX2R.61 As illustrated in Figure 13, the acyclic and cyclic had lost the fluorine atom and gained an oxygen atom,
versions demonstrated very similar potency for binding the suggesting that it was not the core but rather the heterocycle
receptors, supporting the hypothesis that the U-shaped that was the likely site of electrophilic activation. Figure 14
conformation was in fact indicative of the bioactive illustrates the putative mechanism (via epoxide 43) and major
conformation. adduct formed (44) during the incubation of 38 (quinazoline
Working under the assumption of the U-shaped bioactive substructure 42) in both rat and human microsomes in the
conformation, the team began to design novel diazepane cores presence of GSH.
that incorporated alteration of the central ring that enabled or On the basis of this understanding of the mechanism of
enforced the U-shaped conformation. Importantly, it was bioactivation, the team turned its attention toward wide-ranging
recognized that these designs might not only improve potency exploration of heterocyclic motifs to mitigate metabolic
and increase bioavailability due to reduced molecular flexibility activation. A focused effort to design novel heterocycles that
but could also serve to block or hinder access to sites of displayed the desired pharmacokinetic profile in dog and
metabolism and potential bioactivation identified in 36. minimal levels of glutathione adducts discovered that
Bridged analogues such as 37 (Figure 12) existed in a low benzoxazole-containing diazepane analogues possessed excel-
energy U-shaped conformation and afforded modest functional lent dog pharmacokinetics but did not possess the potency of
orexin potency, however, the additional lipophilicity (Log P > 6,6-fused heterocycles such as the quinazolines. The combina-
3.4) incorporated by the addition of a rather small two-carbon tion of the addition of a chlorine atom at the 5-position of the
bridge negatively impacted physiochemical properties leading benzoxazole and installation of the tolyl methyl group on the
to reduced efficacy in rat sleep experiments.62 On the other triazolophenyl amide afforded 39, a potent compound with
hand, the methyldiazepane analogue 38 possessed similar desirable rat and dog pharmacokinetics and surprisingly
lipophilicity (Log P = 3.0) to 36 and maintained excellent rat minimal GSH adduct formation (GSH/IS ratio = 0.1; 97%
sleep efficacy. Many additional cores were discovered from reduction from 38), indicating minimization of the bioactiva-
medicinal chemistry efforts although the team focused most tion pathway for 38 (Figure 15). Further characterization of 39
intently on methyldiazepane as a core with the best aggregate indicated it maintained the clean off-target profile, high brain
properties. Compound 38, containing the fluoroquinazoline penetration, high OX2R occupancy in a humanized rat model,
and desmethyl triazolophenyl amide, arose from efforts to and excellent efficacy in rat and dog sleep studies that earlier
optimize dog pharmacokinetics in the methyldiazepane series. analogues in the series displayed,63 as well as pharmaceutical
It displayed reasonable clearance and bioavailability in the dog properties and a safety profile supportive of clinical develop-
(Cl = 5.2 mL/min/kg; F = 37%) and had an excellent overall ment. Compound 39 entered development as MK-4305,64 later
profile including efficacy in rat sleep studies at a 10-fold lower named suvorexant.
oral dose than 36 (10 mg/kg). The team also developed and After many unsuccessful attempts, a single molecule X-ray
employed a moderate throughput assay to assess bioactivation structure of compound 39 was eventually obtained and
potential by incubating compounds in rat and human liver illustrated that the solid-state conformation was actually an
microsomes in the presence of glutathione comparing adduct extended form (structure not shown).65 This stood in contrast
formation with an internal standard. Unfortunately, the to the U-shaped conformation that guided optimization efforts,
bioactivation liability of 36 was not mitigated by the structural and NMR analysis of 39 also suggested the predominant
alterations that led to 38 as measured by the ratio of the area conformations in solution were extended. Extensive computa-
under the peaks for all GSH adducts relative to the internal tional analysis of diazepanes including 38 and 39 consistently
514 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

followed to discover 39. Figure 17 depicts DORA 39 as it is

bound in the recently reported crystal structure.
A second class of potent DORA molecules was reported by
the Merck team in 2011. These molecules possessed a
stereochemically defined, 2,5-trans-disubstituted piperidine
carboxamide core that owned excellent affinity for OX1R and
OX2R. The initial studies began with known compound 33.
which had good potency but poor preclinical pharmacokinetics
and limiting physicochemical properties (see also Figure 12).
The team discovered that transposition of the ethoxyphenyl
substituent from the 2-position to the 3-position on the
piperidine ring (33 → 45) resulted in a greater than 40-fold
loss in potency at both receptor subtypes (Figure 18). This loss
of potency occurred despite the fact that compound 45
maintained the same atom distance between the piperidine
nitrogen atom and the oxygen of the aryl ether. Indeed, earlier
studies had indicated that the cyclic piperidine was not essential
for potency, and that unconstrained, linear compounds such as
46 retained significant receptor affinity. Linear compounds such
as 46 suffered from high intrinsic clearance and poor
Figure 15. Preclinical characterization of DORA 39. (a) mL/min/kg; physicochemical properties.
(b) humanized OX2R rat occupancy assay.
More detailed conformational analyses were performed to
rationalize the potencies of compounds 33, 45, and 46. The
showed that although the low energy conformation could vary predicted lowest-energy, ground state for compound 33 has the
from U-shaped to extended based on substituents as well as 2-substituent oriented axially on the ring to avoid disfavorable
computational methods employed; in all cases, a U-shaped 1,3-allylic strain between this substituent and the sp2-hybridized
conformation was readily available within 1−2 kcal/mol of the nitrogen atom of the piperidine (Figure 18). Molecular
global minima. The team therefore postulated that a subtle modeling with 33 revealed that a stereoelectronic preference
change in structure upon moving from the 6,6-fused quinazo- for the 2-substituent to adopt an axial orientation enables the
line heterocycle (e.g., 36 and 38) to the 5,6-fused oxazole in 39 two aryl rings to be arrayed coplanar, mimicking the bioactive
altered the energetics slightly such that the extended conformation of DORA 39 (Figures 16 and 17). However,
conformation was now the lowest energy conformation. transposing the 2-substituent in 33 to the 3-position on the
However, the potency of 39 indicated that upon binding to piperidine ring to give 45 relieved the 1,3-allylic strain and
the orexin receptors, the increased enthalpy of binding allowed this substituent to adopt a more stable equatorial
overcame any small entropic penalty brought about by a orientation. Hence, the bioactive U-shaped conformation was a
change in the low energy conformation. high energy conformation, and this likely explains the greater
An X-ray structure of DORA 39 in a stabilized form of the than 40-fold loss in potency from 33 to 45.
OX2R was recently solved and showed that the bound form was The Merck team explored a strategy to induce an axial
in fact a U-shaped conformation as the team had predicted.66 orientation for the 3-alkyl substituent by methyl substitution at
Figure 16 shows the excellent overlay of the bound either α-position adjacent to the sp2-hybridized piperidine
conformation of compound 39 and the low energy U-shaped nitrogen atom. This methyl group might preferentially adopt an
conformation as calculated in the original analysis. As is readily axial orientation and drive the 3-position substituent into an
apparent, the predicted and observed conformations are nearly axial disposition as well provided that the two substituents are
identical, thus validating the design hypothesis the team trans on the piperidine ring. Compound 47, further modified
from 45 with potency-enhancing substitutions on the
carboxamide and on the aryl ether, was selected as the template
for the incorporation of methyl substituents on the core.
Incorporation of a methyl group in the 2-position on 47
provided both the cis- and trans- diastereomers (48 and 49,
respectively) that could be further characterized with respect to
binding affinity and conformational preference. The cis isomer
(48) lost about 2-fold in potency relative to 47, consistent with
the initial hypothesis. In contrast, the trans diastereomer in
DORA 49 was remarkably potent, gaining 20- and 90-fold in
binding affinity for OX1R and OX2R, respectively. The 2-
methylation was found to be more potency-enhancing than the
alternative 6-methylation, and further optimization studies
focused on this disubstituted piperidine core.
Figure 16. Overlay of the ligand-bound X-ray structure of DORA 39 Additional studies were focused on the design of molecules
as determined from PDB coordinates (cyan, structure 4RNB, see related to DORA 49 with improved physicochemical proper-
Figure 17) and the low-energy structure of DORA 39 as calculated in ties, favorable pharmacokinetics, and promising in vivo activity.
Maestro using the OPLS 2005 force field (purple, ref 65). The RMSD From those studies, the team discovered compound 50, a
for non-hydrogen atoms between the two structures is 0.9 Å. potent DORA with good solubility and bioavailability in both
515 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 17. X-ray structure of 39 bound to OX2R as reported in ref 66.

rats and dogs (Figure 19). Low temperature 1H NMR studies focused on the clinical development of DORAs, these data
revealed that the most abundant conformer in solution had the became merely footnotes in the discovery stories. A critical
piperidine ring in a chair conformation with trans-diaxial need for the orexin field at its inception was the identification of
substituent disposition. The major isomer had significant high quality DORA, 2-SORA, and 1-SORA ligands to delineate
through-space correlations (NOE) between the respective receptor specific preclinical and clinical pharmacology. While it
aromatic protons on the pyridine and phenyl rings. A single is clear that many diverse structures in each class of orexin
X-ray structure for 50 (structure not shown, see ref 68) antagonist have been discovered from screening, design, and
confirmed the trans-diaxial arrangement of the 2,5-disubstituted optimization efforts (Figure 3), only a few SORA ligands have
piperidine and only differed from the solution conformation been well characterized in preclinical and clinical settings. The
with rotation of the amide bond. discovery of small molecule DORAs with preclinical profiles
DORA 50 had favorable pharmacokinetics in preclinical suitable for clinical evaluation suggested that the DORA to
species, possessed a clean ancillary profile, high brain SORA pharmacology switching SAR might be useful for the
penetration, excellent OX2R occupancy in humanized rat production of high quality molecules with profiles commensu-
experiments, and dose-dependently promoted sleep in both rate with preclinical and clinical pharmacology studies from
rats and dogs (Figure 19).67 Additionally compound 50 existing clinical candidates.
possessed favorable pharmaceutical properties and a preclinical Figure 20 depicts several recent examples utilizing DORA
toxicology profile supportive of clinical development. Com- clinical candidates, or their close analogues, as lead structures
pound 50 entered development as MK-6096 and was later for the discovery of SORAs. Researchers from Actelion were
named filorexant.68 DORA 50 was found to be more potent able to develop very subtle SAR from clinical candidate DORA
than suvorexant in preclinical EEG studies and could achieve 15 to afford very potent 1-SORAs (Figure 20A). The
higher levels of OX2R receptor occupancy at lower plasma combination of shortening the phenethyl linker by one atom,
concentrations, presumably due to higher unbound plasma modifying the southern aromatic substitution, and methyl to
concentrations in vivo. isopropyl amide conversion afforded 1-SORA 51 (ACT-

335827) which effectively maintained OX1R potency while
increasing selectivity over OX2R 70-fold.69 Compound 51 was
found to be brain-penetrant, orally bioavailable, highly selective
SORAs over a panel of targets, and anxiolytic in the rat fear-potentiated
The discovery of multiple DORA clinical candidates afforded a startle assay upon oral administration. Importantly, the
significant amount of SAR related to selectivity between OX1R anxiolytic effects of 1-SORA 51 were not accompanied by
and OX2R. In some instances, very small changes in structure decreased wakefulness as would be expected from a DORA, and
afforded dramatic effects on potency at either receptor (for these studies suggested this molecule could represent an
example, Figure 4, compounds 10 and 11). As many companies important tool for further pharmacology studies.
516 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 18. Discovery of DORA 50: a potent DORA clinical candidate.

Two additional examples from Merck expanded on the exploration of the terminal heterocycle led to highly potent,
pharmacology switching phenomenon as illustrated in Figure orally bioavailable 2-SORA 53 with rat sleep efficacy.
20B,C. In one study, DORA 38 was not only used as a lead
Surprisingly, the combination of core modification to a
structure in the discovery of clinical candidate DORA 39 but as
a scaffold to explore selectivity. Because of high levels of difluoropiperidine and an isomeric quinoline heterocycle
bioactivation observed in microsomal incubations of DORA 38, completely shifts the selectivity profile to a highly potent 1-
a strategy was adopted to explore isosteric replacements of the SORA 54. This represents an excellent example of accessing a
quinazoline. This effort afforded the truncated pyrimidine
range of selectivity profiles within a single core template. While
found in 2-SORA 52 which possessed similar OX2R potency to
DORA 38 but over 200-fold selectivity over OX1R.70 Upon oral these examples are compelling from a preclinical standpoint,
dosing, compound 52 was found to have sleep efficacy in mice the purposeful use of pharmacology switching as a design
comparable in magnitude and architecture to DORAs in the strategy in the orexin field to produce clinical candidates is rare.
diazepane series. A linker truncation strategy similar to Figure
The next section will describe an example of orexin
20A was also able to provide SORAs in the piperidine DORA
series (Figure 19) as shown in Figure 20C.71 Removal of one pharmacology switching which afforded a clinical candidate
carbon atom from the linker of DORA 50 and wide-ranging for the treatment of insomnia.
517 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

to human Pgp efflux (Figure 22). Compound 60 was also not

an inhibitor or inducer of CYP enzyme isoforms, leading to a
low risk for clinical drug−drug interactions. This compound
possessed moderate clearance, short half-life, and high
bioavailability in rat and dog. This constellation of properties
translated into exquisite efficacy in rat and dog sleep studies.
Upon oral administration of 1 mg/kg of 2-SORA 60 to rats
during their active phase, significant reductions in active wake
and concomitant increases in NREM and REM sleep were
observed which were very comparable to DORA sleep effects.
These effects were mirrored in the dog at doses as low as 0.05
mg/kg, although at this dose REM sleep was less affected. It
should be noted that higher doses of 60 in dogs did indeed
increase REM sleep significantly. On the basis of these data, 2-
SORA 60 was selected for further clinical evaluation and
designated MK-8133.72 To the best of our knowledge, the
discovery of 2-SORA 60 represents the first pharmacology
switching effort to afford an orexin antagonist clinical candidate
to date.

Figure 19. Preclinical characterization of DORA 50. (a) mL/min/kg;

(b) humanized OX2R rat occupancy assay.
Researchers from Merck pursued a structurally distinct 2-SORA

series of triaryl amides that were identified via HTS efforts.
Compound 61 demonstrated promising functional OX2R
PHARMACOLOGY SWITCHING: 2-SORA CLINICAL potency (53 nM, similar to clinical candidate DORA 39,
CANDIDATE FROM MERCK Figure 23) and moderate selectivity over OX1R.73 The modular
The efforts around selectivity evaluation in the piperidine series structure of the lead allowed for rapid analogue synthesis in
described in Figure 20C also revealed a pair of isomeric library format (A- and D-rings) to explore SAR focused on
quinoline analogues with vastly disparate selectivity profiles. potency and selectivity, ultimately culminating in the discovery
Compounds 55 and 56 in Figure 21 differed only by the of 2-SORA 62. This compound was very potent against OX2R,
location of a single nitrogen atom in the heterocyclic ring orally bioavailable in both rat (%F = 55) and dog (%F = 37)
system, however, their functional selectivity profiles differed by and greater than 100-fold selective in a large off-target panel of
over 200-fold. As is detailed in Figure 20, heterocycle assays. These properties allowed for oral evaluation of active
truncation strategies had been successful in the identification phase sleep efficacy in rats, and 62 displayed the hallmark
of highly potent SORAs. To this end, the Merck team explored reductions in active wake and increases in NREM and REM
replacement of the fused quinoline with minimal substitution, sleep observed with previous 2-SORAs and DORAs. One
driven partially by bioactivation concerns from prior efforts in concern in the experiment was the level of selectivity (26× over
the diazepane series, and found that methylpyridine 57 lost 50- OX1R) of the lead might result in significant antagonism of
fold in OX2R binding potency compared to its quinoline OX1R during the in vivo experiment, hence improving
counterpart. Surprisingly, a very similar methylpyridine selectivity was one focus of optimization efforts. Three
analogue (58) of DORA 56 maintained functional OX2R additional medicinal chemistry issues were identified with
antagonism with 49-fold selectivity over OX1R, highlighting the lead 62: potent reversible CYP3A4 inhibition (IC50 = 300 nM),
incredibly subtle SAR surrounding orexin receptor subtype Pgp susceptibility (rat and human), and the potential for
selectivity. A variety of replacements for the methyl group were bioactivation through formation of ortho-quinone or para-
explored, and the 4-cyano-2-pyridine motif in 59 afforded quinone methide intermediates derived from metabolic
comparable OX2R potency with an expanded functional activation of the dimethoxyphenyl motif.
selectivity window over OX1R (290-fold). In addition to Surprisingly, the regioisomeric pyridine C-ring in 63 afforded
potency and selectivity, 2-SORA 59 possessed moderate a dramatic improvement in reversible CYP3A4 inhibition with
lipophilicity (log D = 3.0), high kinetic solubility (148 μM at an IC50 of 38 μM while maintaining the potency and moderate
pH 7), and low clearance in human microsomal incubations selectivity profile of 62. Despite this remarkable profile
suggestive of good pharmaceutical properties. Unfortunately, improvement, 2-SORA 63 suffered from relatively high
59 demonstrated low oral bioavailability in rat and dog (%F < lipophilicity (log D = 3.2) and very high protein binding of
20) which hampered further development. An amide library 99.5% in human plasma. An evaluation of A-ring SAR revealed
was then conducted to procure additional candidates with that replacement of the 3,5-dimethyl phenyl motif with a 3-
improved oral bioavailability. The biaryl pyrimidine amide in methyl-5-pyridyl substituent (64) afforded similar potency and
60, similar to DORA 50 (Figure 19), displayed an excellent 2- selectivity but with significant improvement of physical
SORA profile with similar pharmaceutical properties (log D = properties (log D of 1.5; human plasma protein binding of
2.9, kinetic solubility = 148 μM, micrsomal clearance = 17 mL/ 62%). These improvements were tempered by significant
min/kg) to 2-SORA 59 as well as high crystalline free base susceptibility for human Pgp with an efflux ratio of 4.4
solubility at pH 7.4 of 0.25 mg/mL. Hence, 2-SORA 60 was (substrate ratio ≥3), an undesirable trait for CNS-targeted
selected for in-depth characterization. molecules.74 Reduction of the basicity of the A-ring via methyl
2-SORA 60 demonstrated excellent selectivity over a wide to chlorine replacement afforded 65, a non-Pgp substrate
range of targets, high passive permeability, and no susceptibility (human ratio = 1.7) with improved selectivity over OX1R.
518 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 20. Examples of DORA to SORA pharmacology switching.

Unfortunately, significant levels of GSH adducts were observed suggesting potent target engagement. Binding and functional
for 2-SORA 65 in the microsomal bioactivation assay (see OX2R and OX1R potencies for 2-SORA 66 were very
DORA 39 section, Figure 14), likely due to metabolic consistent across mouse, rat, dog, rhesus, and human cell
activation of the dimethoxyphenyl motif. This concern was lines, supporting the potential for clear sleep efficacy evaluation
mitigated by broad exploration of heterocyclic replacements for of this 2-SORA ligand. Upon active-phase oral dosing of 66 to
the dimethyoxyphenyl motif, and strategic placement of a single mice (100 mg/kg), rats (20 mg/kg), beagle dogs (1 mg/kg),
nitrogen atom in the D-ring of 2-SORA 66 was able to reduce and rhesus monkeys (10 mg/kg), immediate and significant
GSH adduct formation in human microsomal incubations by reductions in active wake and concomitant increases in NREM
85%. 2-SORA 66 maintained OX2R potency, oral bioavail-
and REM sleep were observed in all experiments. An evaluation
ability, limited reversible CYP3A4 inhibition (IC50 = 28 μM),
of unbound concentrations of 66 in each experiment suggested
excellent physical properties (log D = 1.8), and improved
very high OX2R occupancy and very low antagonism of OX1R
selectivity over OX1R to 99-fold. On the basis of these data, 2-
SORA 66 was selected for further characterization. during the course of the sleep experiments. These studies
2-SORA 66 demonstrated high selectivity across a panel of represented the first cross-species evaluation of sleep efficacy
common off-target activities, significant plasma free fraction, for a 2-SORA reported in the literature. Finally, 2-SORA 66
and moderate clearance and oral bioavailability across species was very well tolerated in rat and dog safety studies
which supported in vivo evaluation of 2-SORA pharmacology commensurate with further development. This set of data
(Figure 24). In a humanized OX2R occupancy experiment in supported the advancement of 2-SORA 66 as a preclinical
rats, compound 66 demonstrated 90% occupancy at a plasma candidate for the treatment of insomnia, and 2-SORA 66 was
concentration of 695 nM and a CSF concentration of 52 nM, further designated MK-1064.75
519 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 21. Discovery of 2-SORA 60: a 2-SORA clinical candidate with excellent pharmaceutical properties.

of CYP enzymes, a moderate amount of time-dependent

inhibition of CYP3A4 (TDI) posed a risk for clinical drug−
drug interactions. Because of these concerns, an effort to
identify an additional 2-SORA clinical candidate in the triaryl
amide series was initiated with the aim of improving these two
profile elements.
The medicinal chemistry team hypothesized that protonation
of the C-ring pyridine might afford neighboring group
activation of the amide carbonyl and heightened susceptibility
to amide hydrolysis. A screen of nonbasic C-ring motifs
revealed that a pyridine to phenyl switch was able to confer
complete low pH stability over the course of 24 h, supporting
the mechanistic hypothesis (Figure 25). Unfortunately, many
phenyl C-ring analogues suffered from poor physical properties
and solubility, but installation of a 3-methyl-5-pyridyl A-ring
afforded 2-SORA 67 with excellent low pH stability and
adequate pH 7 solubility (61 μM). These changes to the A- and
C-ring increased clearance in dog significantly (Cl = 27 mL/
min/kg) compared to 66 (15 mL/min/kg), and the team
initiated a scan of a variety of B-ring modifications with the aim
Figure 22. Preclinical characterization of 2-SORA 60. (a) mL/min/kg. of improving the pharmacokinetic profile of 67. Gratifyingly,
the regioisomeric B-ring isonicotinamide in 68 was able to
While 2-SORA 66 demonstrated a profile commensurate maintain OX2R potency, selectivity, pH 2 stability, and lowered
with clinical evaluation for insomnia treatment, two issues arose dog clearance to 15 mL/min/kg. Unfortunately, TDI evaluation
during preclinical development of the compound. First, of 2-SORA 68 revealed no improvement compared to the
pharmaceutical salt form evaluation revealed a significant benchmark 66 (Kinact/Ki = 0.012 min−1 μM−1) with a Kinact/Ki
amount of amide hydrolysis at low pH (∼2), which = 0.013 min−1 μM−1. Exploration of C-ring motifs in the
necessitated using the free base of 2-SORA 66 in a stabilized isonicotinamide B-ring series afforded the 2-thiazole C-ring in
amorphous dispersion for clinical studies. Second, although 69 as an isosteric replacement of the phenyl motif. TDI studies
compound 66 was not a potent reversible inhibitor or inducer demonstrated a significant reduction in TDI risk with a Kinact/Ki
520 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 23. Discovery of 2-SORA 66: the first 2-SORA to reach clinical evaluation for the treatment of insomnia.

= 0.004 min−1 μM−1 and, importantly, maintenance of low pH

stability. The realization of low pH stability for 2-SORA 69 was
likely due to the nonbasic nature of the 2-thiazole motif with a
calculated pKa of 0.3 (versus 3.2 for the 2-pyridyl C-ring). The
achievement of the stability and TDI goals in a highly potent 2-
SORA suggested that 69 was an excellent candidate for
additional characterization.
2-SORA 69 maintained the excellent off-target profile of its
predecessor, adequate free fraction in both dog and rat, and
target engagement in the humanized OX2R occupancy assay in
rat (Figure 26). Compound 69 demonstrated low to moderate
clearance and short half-lives in dog and rat as well as
acceptable bioavailability in both species. Oral EEG studies in
rat and dog confirmed potent sleep efficacy similar to 2-SORA
66 at low doses. Preclinical safety studies in a similar paradigm
to 2-SORA 66 supported advancement of the compound into
clinical development and on the strength of this data 2-SORA
69 was designated MK-3697.76


Eight orexin antagonists have reached human clinical trials with
at least four of them completing phase II efficacy studies:
Figure 24. Preclinical characterization of 2-SORA 66. (a) mL/min/kg; DORA 15 (Figure 5), DORA 28 (Figure 10), DORA 39
(b) humanized OX2R rat occupancy assay. (Figure 15), and DORA 50 (Figure 19). These DORAs all have
provided dose-dependent increases in sleep efficiency with
varying levels of efficacy in the clinical registration end points of
521 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Figure 25. Discovery of 2-SORA 69: a 2-SORA clinical candidate with improved formulation properties and DDI risk.

pharmacodynamic measures and reports of adverse events.79 In

that study, DORA 15 was found to have a short Tmax (0.7−2.3
h) with a biphasic PK profile. The elimination half-life varied
from 13.1 to 19.0 h and increased with dose. No cataplexy- or
narcolepsy-related side effects were observed, and drug-related
changes in body sway and smooth pursuit eye movements were
generally less than those produced by a zolpidem comparator.
DORA 15 was generally well tolerated in healthy volunteers,
with reports of somnolence, dizziness, disturbed attention, and
fatigue reported occurring with greater frequency at doses
greater than 200 mg. There were no drug-related effects on
body weight, electrocardiogram, clinical laboratory signs, and
other vital signs. Pharmacodynamic assessments included a
visual analogue scale (VAS) for subjective alertness, which
indicated dose dependent reductions in alertness at 400 and
1000 mg. Subjective alertness returned to baseline approx-
imately 6 h following a single dose of 400 mg and
approximately 10 h after a dose of 1000 mg. The absolute
magnitude of this result was reported to be similar to zolpidem
(10 mg) with a more sustained effect on alertness.
Figure 26. Preclinical characterization of 2-SORA 69. (a) mL/min/kg; On the basis of the encouraging phase I data in healthy
(b) humanized OX2R rat occupancy assay. volunteers, DORA 15 was advanced into phase II studies,
where it was evaluated in 161 male and female primary
reducing time to sleep onset (latency to persistent sleep; LPS) insomnia patients at doses of 50−400 mg compared to
and increasing sleep maintenance (wake after sleep onset; placebo.80 The primary end point in this study was sleep
WASO). Clinical development of DORA 15 and DORA 28 was efficiency (SE) as measured by polysomnography (PSG) with
terminated, while DORA 39 has received regulatory approval in secondary end points of LPS, WASO, and safety and
the U.S. and Japan.77 DORA 50 has completed phase II studies tolerability. Significant increases in sleep efficiency and total
and has been investigated in other neurological indications.78 sleep time (TST) were observed after a single dose of
Additional DORAs have been reported to have entered clinical almorexant at 200 and 400 mg. DORA 15 also reduced time to
development (Actelion, DORA 22, Figure 8; Eisai, vide infra), sleep onset at the highest dose and decreased WASO at 200
and two OX2R-selective antagonists are reported to be in and 400 mg with good tolerability (Table 2).
clinical development (Merck, 2-SORA 66, Figure 24; Janssen, On the basis of favorable phase II data, DORA 15 was
vide infra). advanced into phase III studies (RESTORA1) in patients with
Actelion was the first pharmaceutical company to report chronic insomnia, and GlaxoSmithKline entered into a
human clinical data for a DORA molecule and establish that collaborative agreement with Actelion in 2008 to codevelop
orexin antagonism could provide therapeutic benefit for the DORA 15.81 In January 2011, Actelion announced that clinical
treatment of sleep disorders. DORA 15 (almorexant) was development for DORA 15 was stopped due to clinical safety
initially explored in a rising dose study to healthy males from 1 issues82 which were subsequently identified as infrequent
to 1000 mg and compared to zolpidem with respect to transient liver enzymes increases.
522 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Table 2. Mean Changes Relative to Placebo on Objective due to the emergence of a reported, but unspecified, preclinical
Sleep Parameters after a Single Dose of DORA 15 to toxicity.86
Patients with Primary Insomnia Merck’s first orexin antagonist clinical candidate, DORA 39
(suvorexant), entered clinical development in 2007. In phase I
50 mg 100 mg 200 mg 400 mg
studies, DORA 39 was well tolerated in healthy volunteers, with
sleep efficiency (%) 3.3 4.6 8.2* 14.4*a peak plasma levels achieved at 1.5−4 h and a terminal plasma
LPS (min) −5.7 −10.4 −10.4 −18.0 half-life of 8−14 h.87 When dosed in the evening, next day
WASO (min) −6.7 −20.1 −34.3*a −54.0*a residual sedation was not observed with suvorexant at 10 and
TST (min) 15.8 21.4 39.3*a 69.7*a 50 mg doses while these same doses provided dose-dependent
*P < 0.001. increases in overall SE and reductions in WASO and LPS.
Results from the phase IIb study demonstrated that DORA 39
GlaxoSmithKline’s dual orexin receptor antagonist, DORA was superior to placebo in improving SE on the first night of
28 (28, Figure 10), was investigated in seven completed clinical treatment as well as at the end of 4 weeks in patients with
studies (six phase I and one phase II).83 In initial single rising primary insomnia (Tables 4 and 5).88 Improvements in SE
dose studies, DORA 28 was well-tolerated across doses of 10−
80 mg and provided proportional increases in exposure across Table 4. Treatment Effects Relative to Placebo on Objective
the dose range.84 Plasma half-lives ranged from 4 to 7 h with Sleep Parameters after Administration of DORA 39 to
rapid absorption. DORA 28 was administered in three groups Insomnia Patients on Night 1
of healthy volunteers to assess drug effects on safety,
pharmacokinetics, and EEG measures with daytime dosing 10 mg 20 mg 40 mg 80 mg
and to assess objective measures of sleep by PSG following sleep efficiency (%) 5.2 7.6*a 10.8*a 12.9*a
evening dosing. DORA 28 effects on sleep induction and LPS (min) −3.4 −9.4 −23.1*a −25.4*a
maintenance were assessed in healthy volunteers at 30 and 60 WASO (min) −21.2*a −24.7*a −33.9*a −36.8*a
mg. Statistically significant improvements on TST versus TST(min) 25.1 36.2*a 52.4*a 61.9*a
placebo were observed at 30 and 60 mg. DORA 28 also a
*P < 0.001.
reduced LPS and reduced WASO at both doses. Neither dose
impaired cognition as measured by a digit symbol substitution Table 5. Treatment Effects Relative to Placebo on Objective
test (DSST) in the morning following evening drug Sleep Parameters after Administration of DORA 39 to
administration. Insomnia Patients on Night 28
In 2007, GSK announced that DORA 28 had advanced to
phase II clinical trials. DORA 28 was studied in a phase II 10 mg 20 mg 40 mg 80 mg
multidose efficacy study with 52 male patients that met criteria sleep efficiency (%) 4.7 10.4*a 7.8*a 7.6*a
for a diagnosis of primary insomnia.85 The drug was LPS (min) −2.3 −22.3*a −3.8 −9.5
administered for two consecutive nights 90 min before bedtime, WASO (min) −21.4*a −28.1*a −33.2*a −28.9*a
and the sleep promoting effects were assessed by PSG and TST(min) 22.3 49.9*a 36.8*a 36.6*a
compared to placebo. DORA 28 provided significant, dose- a
*P < 0.001.
dependent increases in SE and TST while reducing LPS and
WASO (Table 3). The drug was well tolerated, and the effects were noted at all doses (10, 20, 40, and 80 mg). DORA 39 also
showed favorable outcomes in the secondary end points of
Table 3. Treatment Effects Relative to Placebo on Objective reduced WASO at all doses and reduced LPS at a doses of 40
Sleep Parameters after Administration of DORA 28 to Male and 80 mg. In these studies, DORA 39 was well tolerated, with
Insomniacs (Mean of Two Consecutive Nights) the most common adverse event reported to be somnolence,
10 mg 30 mg 60 mg which showed dose-related increases. No pattern was seen
sleep efficiency (%) 4.7*a
suggestive of rebound insomnia or withdrawal after 4 weeks of
LPS (min) −26.1*a −33.0*a −43.7*a
dosing. There was also no consistent evidence for next day
WASO (min) +3.2 −18.4*a −29.0*a
residual effects as measured by standard cognitive testing
TST(min) 22.4*a 49.7*a 69.8*a
(DSST and DSCT) 9 h after dosing at the end of 4 weeks of
*P < 0.001.
In 2010, Merck announced that DORA 39 had entered into
three phase III trials. Two pivotal studies enrolled over 2000
were described by the authors as being comparable to the nonelderly and elderly patients for 3 month trials at 170 sites
hypnotic effect produced by benzodiazepines, nonbenzodiaze- comparing suvorexant at two dose levels versus placebo for 3
pine GABA modulators, and sedating antidepressants. The month duration.89 Efficacy was assessed at week 1, month 1,
most common adverse events reported in this study were and month 3 by PSG on WASO and LPS end points and by
headache, dry mouth, and nasopharyngitis. patient reported total sleep time and time to sleep onset. In
Additional clinical studies revealed that DORA 28 increased these studies, a high dose (40 and 30 mgs for nonelderly and
exposure of coadministered simvastatin in a drug−drug elderly, respectively) and a low dose (20 and 15 mgs for
interaction study. With a 30 mg dose of DORA 28, total nonelderly and elderly, respectively) of DORA 39 was
plasma exposure of coadministered simvastatin increased compared to placebo. Mean treatment differences from placebo
greater than 6-fold after 15 consecutive days of codosing (see for the high dose groups in PSG parameters in trials 1 and 2 are
ref 84). Consistent with these observations, DORA 28 was shown in Table 6. DORA 39 provided benefit in reducing time
reported to be a potent inhibitor of CYP3A4 in vitro. DORA 28 to sleep onset and improved sleep maintenance at all time
was placed on clinical hold in late 2007 from phase II studies points except on LPS at month 3. Mean treatment differences
523 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

Table 6. Efficacy for DORA 39 in Insomnia Patients: High Dose 40/30 mg over 3 Monthsa
night 1 month 1 month 3
trial 1 trial 2 trial 1 trial 2 trial 1 trial 2
LPS (min) −10.3* b
−21.7* b
−11.2* b
−12.1* b
−9.4* b
WASO (min) −38.4*b −42.0*b −26.3*b −29.4*b −22.9*b −29.4*b
Difference between placebo and suvorexant in least squares mean change from baseline. b*P < 0.001.

Table 7. Efficacy for Suvorexant in Insomnia Patients: Low Dose 20/15 mg over 3 Monthsa
night 1 month 1 month 3
trial 1 trial 2 trial 1 trial 2 trial 1 trial 2
LPS (min) −9.6*b −12.4 −10.3*b −7.8 −8.1 −0.3
WASO (min) −32.5*b −37.0*b −26.4*b −24.1*b −16.6*b −31.1*b
Difference between placebo and DORA 39 in least squares mean change from baseline. b*P < 0.001.

Figure 27. Representative compounds from companies with reported interest in clinical or preclinical development of orexin antagonists. For
additional information on compounds 70−74, please see refs 106, 98, 107, 101, and 108, respectively.

from placebo for the low dose groups in PSG parameters for using the lowest effective doses with insomnia drugs.91 A
trials 1 and 2 are summarized in Table 7. Improvements in prescribing label for the approved doses of DORA 39 is
subjective measures of sleep onset and sleep maintenance were available.92
also significant versus placebo, and patients reported improved Merck has disclosed clinical development activity for a
perceptions of sleep quality and feeling refreshed in the second DORA candidate, DORA 50 (filorexant). Detailed
morning. The higher doses of DORA 39 appeared to be more clinical data for DORA 50 have not been published, although
effective than the lower doses; however, the doses were not data has been presented at several scientific meetings.93
compared directly. In these studies, DORA 39 was well- Interestingly, DORA 50 has been studied in indications beyond
tolerated and rates of discontinuations and adverse events were primary insomnia, including migraine prophylaxis, postherpetic
generally comparable between the suvorexant and placebo neuralgia, and as adjunct therapy for major depressive
groups. The most common AE that was increased for DORA disorder.94 DORA 50 was evaluated at a single dose level (10
39 was next day somnolence which trended higher at the high mg) in 120 patients with frequent, episodic migraines.95 In this
doses. study, DORA 50 was dosed prior to bedtime and did not show
A third phase III study was conducted with DORA 39 which efficacy on any migraine or headache outcomes. Efficacy for
investigated the safety and efficacy of 40/30 mg (nonelderly/ DORA 50 in other indications has not been disclosed.
elderly patients) of suvorexant in patients for one year.90 In this Two additional DORA molecules have entered human
trial, DORA 39 was generally safe and well tolerated, and the clinical studies. A single-ascending dose study with DORA 22
most common adverse event was reported to be somnolence. (22, Figure 8) in healthy volunteers was reported with both
Efficacy for DORA 39 was maintained for the one year duration placebo and DORA 15 control groups.96 DORA 22 was
of the study in terms of subjective TST and subjective LPS explored across a broad dose range (5−1500 mg) and
without evidence of tolerance. In reviewing the totality of compared to placebo across a battery of pharmacodynamics
clinical data on DORA 39, the US Food and Drug assessments. DORA 22 was well tolerated, with the most
Administration approved the use of lower doses of suvorexant, common adverse events reported to be sleepiness, fatigue, and
5, 10, 15, and 20 mg, consistent with the agency’s position on disturbance in attention at higher doses. Tmax for DORA 22
524 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

varied from 1.5 to 4 h, with a trend toward longer Tmax at higher 1. Genetic Evidence of Disease-Relevant Biology. Studies that
doses. The plasma half-life was approximately 10 h and varied immediately followed the discovery of orexins firmly
with dose. As was seen with almorexant, increasing doses of established the importance of the orexin system in the
DORA 22 reduced subjective alertness (via VAS), with a sleep/wake cycle via genetic evidence in rodents and
maximum effect observed at 1000 mg. This maximum dogs as well as in human patients suffering from
pharmacodynamic effect for DORA 22 at 1000 mg matched narcolepsy. These findings supported the notion that
the effect of DORA 15 at 400 mg used as an active comparator orexin antagonists would be effective in the treatment of
in this study. The authors note that the pharmacokinetic profile insomnia.104
for DORA 22 at 400 mg is not ideal for a sleep-promoting 2. Application of a Translatable Biomarker Strategy. The
compound given the delayed absorption observed for this drug. orexin system is highly conserved across species and data
Clinical data from Eisai for DORA 71 (E2006, Figure 27) has from preclinical sleep studies provided potential for
been presented and publication is in press.97,98 DORA 71 is a translation of qualitative and quantitative EEG data from
potent DORA and was studied at doses of 1, 2.5, 5, 10, 15, and a preclinical setting to clinical studies in patients suffering
25 mg in a placebo-controlled phase II study with SE as the from insomnia. This biomarker strategy has proven to
primary end point for 15 days. DORA 71 was reported to effectively translate from preclinical studies to man.
improve sleep efficiency at all doses and reduce both LPS and 3. Highly Successf ul HTS Campaigns. The chemical matter
WASO at all dose levels greater than 2.5 mg. The most covered in this perspective originated almost exclusively
common treatment-related adverse events were somnolence, from HTS efforts within the pharmaceutical industry.
headache, and, less frequently, sleep paralysis. The only dose The wealth of structural diversity that effectively engaged
group to show a statistically significant increase in next day the orexin receptors afforded ample opportunities for
sleepiness was the 25 mg dose. Although pharmacodynamic creative solutions to medicinal chemistry issues encoun-
data have been shared from studies in healthy volunteers and in tered during drug discovery programs.
patients, human pharmacokinetic data (Tmax, T1/2) have not 4. Bioactive Conformation Analysis As an Inspiration for
been disclosed. On the basis of the phase II data, Eisai Co. Medicinal Chemistry Design. The hypothesis of a U-
announced the intent to advance DORA 71 to phase III clinical shaped or π-stacked bioactive conformation for DORAs
studies. was initially suggested due to NMR analysis of leading
Two 2-SORAs are known to have entered human clinical molecules and conformationally restricted analogues.
studies. 2-SORA 66 (66, Figure 24) was the first 2-SORA This bioactive conformation hypothesis was utilized to
known to have entered clinical trials. Compound 66 was design new scaffolds and afforded DORAs with improved
explored in healthy volunteers across a 5−250 mg dose range to potency and efficacy. Gratifyingly, this hypothesis has
assess for safety, tolerability, and pharmacodynamic effects.99 recently been confirmed by X-ray crystallographic studies
After oral administration, 2-SORA 66 was reported to have a and continues to impact current medicinal chemistry
short T1/2 (1.6−4.0 h) with a rapid Tmax (1−2 h). 2-SORA 66 efforts throughout the orexin field.105
provided dose-dependent reductions in alertness as measured 5. Incorporation of Bioactivation Assays into Medicinal
by VAS, providing a peak decrease at 100 mg. 2-SORA 66 was
Chemistry Programs. While somewhat controversial,
further evaluated in a PSG study in healthy subjects at single
there is ample evidence that bioactivation of drug
doses of 50, 120, and 250 mg versus placebo. All doses
candidates can result in idiosyncratic toxicity increasing
increased SE and LPS, while the two higher doses provided
the risk of candidate failure. Two DORA clinical
significant effects on WASO relative to placebo. All doses
candidates were shown to form reactive metabolites
increased TST without changing REM/NREM proportions in
that possessed the potential to interact with biologically
the healthy subjects similar to the effects observed with DORAs
relevant nucleophiles. These observations might have
in healthy subjects.100 A second 2-SORA, JNJ-42847922 (2-
impacted the development of these clinical candidates.
SORA 73, Figure 27), has been disclosed by Janssen
The incorporation of in vitro bioactivation assays
Pharmaceuticals.101 Interestingly, this orexin antagonist was
relatively early in medicinal chemistry efforts afforded a
evaluated in a PSG study in patients with major depressive
significant reduction in bioactivation potential for several
disorder in a phase Ib study; clinical data on this molecule have
not been disclosed. clinical candidates.

The level of interest in orexin antagonists remains high as a
SUMMARY AND FUTURE PERSPECTIVE number of companies are reported to be active in clinical trials
or preclinical programs focused on the treatment of insomnia
Medicinal chemistry endeavors in the orexin antagonist field (Figure 27).106−108 Future efforts in the field could reach
over the past 17 years have resulted in the publication of over
beyond insomnia, with 1-SORAs demonstrating preclinical
200 patent applications by 15 pharmaceutical companies, the
efficacy in models of anxiety,69 2-SORAs and DORAs
public disclosure of 11 clinical candidates,102 and the FDA
approval of Belsomra (suvorexant), the first marketed orexin demonstrating efficacy in preclinical models of addiction and
antagonist for the treatment of insomnia.103 One might ask in a relapse,109 and orexin agonists possessing significant therapeutic
retrospective sense: what drove the field to this level of activity? potential for patients suffering from narcolepsy or as alerting
What were the key factors that supported the discovery of a agents.110 Excitingly, the crystal structure of DORA 39 bound
diverse array of clinical candidates and the eventual launch of a to OX2R suggests additional opportunities for structure-based
first-in-class product? From our view, here are a few key drug design to impact future orexin drug discovery efforts. With
program elements that contributed to successful candidate these preclinical results and the tools in hand, the orexin field
progression. will be an interesting landscape to monitor for years to come.
525 DOI: 10.1021/acs.jmedchem.5b00832
J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry


AUTHOR INFORMATION root-mean-square deviation; SAR, structure−activity relation-

Corresponding Author ship; SE, sleep efficiency; SORA, selective orexin receptor
*Phone: + 1-215-652-8257. Fax: + 1-215-652-7310. E-mail: antagonist; T1/2, half-life; TDI, time-dependent inhibition of CYP3A4; Tmax, time to maximum concentration post drug
administration; TPSA, topological polar surface area; TST, total
sleep time; VAS, visual analogue score; WASO, wake after sleep
The authors declare no competing financial interest. onset

Anthony J. Roecker received his Ph.D. from The Scripps Research REFERENCES
Institute under the guidance of Professor K. C. Nicolaou and joined
Merck Discovery Chemistry, West Point, in 2004. He is a Principal (1) Gershell, L. Insomnia market. Nat. Rev. Drug Discovery 2006, 5,
Scientist in the Lead Optimization Department, and his work focuses
(2) Riemann, D.; Spiegelhalder, K.; Feige, B.; Voderholzer, U.;
on neuroscience programs. A.J. has been involved in both the early and Berger, M.; Perlis, M.; Nissen, C. The hyperarousal model of
late stages of discovery programs, which have resulted in the successful insomnia: A review of the concept and its evidence. Sleep Med. Rev.
delivery of high quality molecules into clinical development. A.J.’s 2010, 14, 19−31.
interest in organic chemistry began as an undergraduate at The Ohio (3) Stoller, M. K. Economic effects of insomnia. Clin. Ther. 1994, 16,
State University, where he graduated with honors in 1999. 873−897.
(4) Daley, M.; Morin, C. M.; LeBlanc, M.; Gregoire, J.-P.; Savard, J.
Christopher D. Cox received his Ph.D. from Johns Hopkins
The economic burden of insomnia: Direct and indirect costs for
University and was a National Institutes of Health (NIH) postdoctoral individuals with insomnia syndrome, insomnia symptoms, and good
fellow at Columbia University. Chris joined Merck Discovery sleepers. Sleep 2009, 32, 55−64.
Chemistry, West Point, in 2001, where he currently serves as a (5) Riemann, D.; Perlis, M. L. The treatments of chronic insomnia: A
Director of Exploratory Chemistry and colead of the Antiviral Early review of benzodiazepine receptor agonists and psychological and
Discovery Unit. In this role, Chris is responsible for building and behavioral therapies. Sleep Med. Rev. 2009, 13, 205−214.
managing Merck’s prelead optimization portfolio in the antiviral area. (6) Nutt, D. J.; Stahl, S. M. Searching for the perfect sleep: The
Chris has been directly involved in the discovery of six preclinical drug continuing evaluation of GABAA receptor modulators as hypnotics. J.
candidates, including suvorexant. Psychopharmacol. 2010, 24, 1601−1612.
(7) Dockhorn, R. J.; Dockhorn, D. W. Zolpidem in the treatment of
Paul J. Coleman received his Ph.D. from Indiana University and was a short-term insomnia: A randomized, double-blind, placebo-controlled
National Institutes of Health (NIH) postdoctoral fellow at Harvard clinical trial. Clin. Neuropharmacol. 1996, 19, 333−340.
University. Paul joined Discovery Chemistry, West Point, in 1996, (8) MacFarlane, J.; Morin, C. M.; Montplaisir, J. Hypnotics in
where he currently serves as Executive Director of Exploratory insomnia: The experience of zolpidem. Clin. Ther. 2014, 36, 1676−
Chemistry, supervising several preclinical discovery teams. Paul’s work 1701.
has helped identify clinical candidates for the treatment of (9) Toner, L. C.; Tsambiras, B. M.; Catalano, G.; Catalano, M. C.;
osteoporosis, cancer, infectious diseases, and sleep disorders, including Cooper, D. S. Central nervous system side effects associated with
zolpidem treatment. Clin. Neuropharmacol. 2000, 23, 54−58.
the approved drug suvorexant. Paul is an alumnus of the University of
(10) Yang, W.; Dollear, M.; Muthukrishnan, S. R. One rare side effect
Chicago and is the author of over 150 peer-reviewed publications and of zolpidem − sleepwalking: a case report. Arch. Phys. Med. Rehabil.
patent applications. 2005, 86, 1265−1266.

We thank Dr. Anthony L. Gotter and Dr. Christopher J.
(11) Yun, C.-H.; Kim, H.; Park, S.-H. Sleep-related eating as a side
effect of drugs for insomnia. In Handbook of Nutrition, Diet, And Sleep;
Preedy, V. R., Patel, V. B., Le, L.-A., Eds.; Wageningen Academic
Publishers: Wageningen, The Netherlands, 2013; Vol. 3, 389−398.
Winrow for discussions and review of this manuscript. We also (12) Gunja, N. In the Zzz zone: The effects of Z-drugs on human
like to thank Sharon O’Brien for preparation of Figures 1 and 2 performance and driving. J. Med. Toxicol. 2013, 9, 163−171.
and Dr. Kerim Babaoglu for preparation of Figures 16, 17, and (13) Farkas, R. H.; Unger, E. F.; Temple, R. Zolpidem and driving
the Table of Contents graphic. impairment − Identifying persons at risk. N. Engl. J. Med. 2013, 369,

CBT, cognitive behavioral therapy; cLogP, calculated octanol/
(14) FDA Requests Label Change for All Sleep Disorder Drug Products;
US Food and Drug Administration: Silver Spring, MD, 2007; March
14, 2007;
water partition coefficient; CNS, central nervous system; CSF, PressAnnouncements/2007/ucm108868.htm.
cerebrospinal fluid; CYP, cytochrome P450; DORA, dual (15) (a) FDA Approves New Label Changes and Dosing for Zolpidem
orexin receptor antagonist; DSCT, digit symbol coding test; Products and a Recommendation to Avoid Driving the Day after Using
DSM-APA, Diagnostic and Statistical Manual of the American Ambien CR; US Food and Drug Administration: Silver Spring, MD,
Psychiatric Association; DSST, digit symbol substitution test; May 14, 2013;
EEG, electroencephalography; EMG, electromyography; htm; (b) : Risk of Next-Morning Impairment after Use of Insomnia
FLIPR, fluorescence imaging plate reader; GABA, gamma- Drugs; FDA Requires Lower Recommended Doses for Certain Drugs
aminobutyric acid; GPCR, G-protein coupled receptor; GSH, Containing Zolpidem (Ambien, Ambien DR, Edluar, and Zolpimist); US
glutathione; HBD, hydrogen bond donor; HTS, high Food and Drug Administration: Silver Spring, MD, January 10, 2013;
throughput screen; LPS, latency to persistent sleep; MW,
(16) Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R.
molecular weight; NMR, nuclear magnetic resonance; NOE,
M.; Tanaka, H.; Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.;
nuclear Overhauser effect; NREM, nonrapid eye movement; Wilson, S.; Arch, J. R. S.; Buckingham, R. E.; Haynes, A. C.; Carr, S. A.;
OX1R, orexin 1 receptor; OX2R, orexin 2 receptor; OX-A, Annan, R. S.; McNulty, D. E.; Liu, W.-S.; Terrett, J. A.; Elshourbagy,
orexin A peptide; OX-B, orexin-B peptide; pKa, the negative N. A.; Bergsma, D. J.; Yanagisawa, M. Orexins and orexin receptors: A
logarithm of the acid ionization constant; Pgp, P-glycoprotein; family of hypothalamic neuropeptides and G protein-coupled
PSG, polysomnography; REM, rapid eye movement; RMSD, receptors that regulate feeding behavior. Cell 1998, 92, 573−585.

526 DOI: 10.1021/acs.jmedchem.5b00832

J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

(17) Arch, J. R. S.; Williams, G.; Wilson, S. Orexins and obesity. (35) Scifinder search using “SB-334867” in March 2015.
Neuroscience News 1999, 2, 37−42. (36) It should be noted that SB-334867 has been reported to be
(18) de Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.-B.; Foye, P. E.; hydrolytically unstable and should be treated carefully when
Danielson, P. E.; Fukuhara, C.; Battenberg, E. L. F.; Gautvik, V. T.; performing pharmacology studies. See: McElhinny, C. J., Jr.; Lewin,
Bartlett, F. S., II; Frankel, W. N.; van den Pol, A. N.; Bloom, F. E.; A. H.; Mascarella, S. W.; Runyon, S.; Brieaddy, L.; Carroll, F. I.
Gautvik, K. M.; Sutcliffe, J. G. The hypocretins: Hypothalamus-specific Hydrolytic instability of the important orexin 1 receptor antagonist
peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U. S. A. SB-334867: Possible confounding effects on in vivo and in vitro
1998, 95, 322−327. studies. Bioorg. Med. Chem. Lett. 2012, 22, 6661−6664.
(19) Gotter, A. L.; Webber, A. L.; Coleman, P. J.; Renger, J. J.; (37) Langmead, C. J.; Jerman, J. C.; Brough, S. J.; Scott, C.; Porter, R.
Winrow, C. J. International union of basic and clinical pharmacology. A.; Herdon, H. J. Characterization of the binding of [3H]-SB-674042,
LXXXVI. Orexin receptor function, nomenclature and pharmacology. a novel nonpeptide antagonist, to the human orexin-1 receptor. Br. J.
Pharmacol. Rev. 2012, 64, 389−420. Pharmacol. 2004, 141, 340−346.
(20) Lin, L.; Faraco, J.; Li, R.; Kadotani, H.; Rogers, W.; Lin, X.; Qiu, (38) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li, X.; Aluisio, L.
X.; de Jong, P. J.; Nishino, S.; Mignot, E. The sleep disorder canine E.; Phuong, V. K.; Dvorak, C. A.; Lovenberg, T. W.; Carruthers, N. I.;
narcolepsy is caused by a mutation in the hypocrein (orexin) receptor Jones, T. K. Novel substituted 4-phenyl-[1,3]dioxanes: Potent and
2 gene. Cell 1999, 98, 365−376. selective orexin receptor 2 (OX2R) antagonists. Bioorg. Med. Chem.
(21) Chemelli, R. M.; Willie, J. T.; Sinton, C. M.; Elmquist, J. K.; Lett. 2004, 14, 4225−4229.
Scammell, T.; Lee, C.; Richardson, J. A.; Williams, S. C.; Xiong, Y.; (39) Fraser, I.; Aluisio, L.; Yun, S.; Shelton, J.; Lord, B.; Sutton, S.;
Kisanuki, Y.; Fitch, T. E.; Nakazato, M.; Hammer, R. E.; Saper, C. B.; Jiang, X.; Dvorak, C.; Dugovic, C.; Bonaventure, P.; Carruthers, N.;
Yanagisawa, M. Narcolepsy in orexin knockout mice: Molecular Lovenberg, T. In vivo neurochemical characterization of a selective
genetics of sleep regulation. Cell 1999, 98, 437−451. orexin-2 receptor antagonist. Society for Neuroscience Meeting, San
(22) Thannickal, T. C.; Moore, R. Y.; Nienhuis, R.; Ramanathan, L.; Diego, CA, November 13−17, 2010, poster 167.17.
Gulyani, S.; Aldrich, M.; Cornford, M.; Siegel, J. M. Reduced number (40) Hirose, M.; Egashira, S.-I.; Goto, Y.; Hashihayata, T.; Ohtake,
of hypocretin neurons in human narcolepsy. Neuron 2000, 27, 469− N.; Iwaasa, H.; Hata, M.; Fukami, T.; Kanatani, A.; Yamada, K. N-acyl
474. 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: The first orexin-2 re-
(23) Nishino, S.; Ripley, B.; Overeem, S.; Lammers, G. J.; Mignot, E. ceptor selective non-peptidic antagonist. Bioorg. Med. Chem. Lett. 2003,
Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000, 13, 4497−4499.
355, 39−40. (41) Aissaoui, H.; Clozel, M.; Weller, T.; Koberstein, R.; Sifferlen, T.;
(24) Asahi, S.; Egashira, S.-I.; Matsuda, M.; Iwaasa, H.; Kanatani, A.; Fischli, W. Sulfonylamino-acetic acid derivatives. WO 2004033418,
Ohkubo, M.; Ihara, M.; Sakurai, R.; Morishima, H. Structure−activity April 22, 2004.
relationship studies on the novel neuropeptide orexin. Peptide Sci. (42) Aissaoui, H.; Clozel, M.; Fischli, W.; Koberstein, R.; Sifferlen,
1999, 36, 37−40. T.; Weller, T. 7,8,9,10-tetrahydro-6H-azepino-6,7,8,9-tetrahydro-pyr-
(25) Asahi, S.; Egashira, S.-I.; Matsuda, M.; Iwaasa, H.; Kanatani, A.; ido and 2,3-dihydro-2H-pyrrolo[2,1-B]-quinazolinone derivatives. WO
Ohkubo, M.; Ihara, M.; Morishima, H. Development of an orexin-2 2004004733, January 15, 2004.
selective agonist [Ala11, D-Leu15]orexin-B. Bioorg. Med. Chem. Lett. (43) Bergman, J. M.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.;
2003, 13, 111−113. Reiss, D. R.; Ransom, R. W.; Meacham Harrell, C. M.; Pettibone, D. J.;
(26) Chen, Q.; de Lecea, L.; Hu, Z.; Gao, D. The hypocretin/orexin Lemaire, W.; Murphy, K. L.; Li, C.; Prueksaritanont, T.; Winrow, C. J.;
system: An increasingly important role in neuropsychiatry. Med. Res. Renger, J. J.; Koblan, K. S.; Hartman, G. D.; Coleman, P. J. Proline bis-
Rev. 2015, 35, 152−197. amides as potent dual orexin receptor antagonists. Bioorg. Med. Chem.
(27) Sakurai, T.; Mieda, M. Connectomics of orexin-producing Lett. 2008, 18, 1425−1430.
neurons: Interface of systems of emotion, energy homeostasis and (44) Aissaoui, H.; Koberstein, R.; Zumbrunn, C.; Gatfield, J.;
arousal. Trends Pharmacol. Sci. 2011, 32, 451−462. Brisbare-Roch, C.; Jenck, F.; Treiber, A.; Boss, C. N-glycine-
(28) Scammell, T. E.; Winrow, C. J. Orexin receptors: Pharmacology sulfonamides as potent dual orexin 1/orexin 2 receptor antagonists.
and therapeutic opportunities. Annu. Rev. Pharmacol. Toxicol. 2011, 51, Bioorg. Med. Chem. Lett. 2008, 18, 5729−5733.
243−266. (45) Koberstein, R.; Aissaoui, H.; Bur, D.; Clozel, M.; Fischli, W.;
(29) Scifinder search using “orexin antagonists” and limiting Jenck, F.; Mueller, C.; Nayler, O.; Sifferlen, T.; Treiber, A.; Weller, T.
references to patent filings in March 2015. Tetrahydroisoquinolines as orexin receptor antagonists: Strategies for
(30) Tautermann, C. S. GPCR structures in drug design, emerging lead optimization by solution-phase chemistry. Chimia 2003, 57, 270−
opportunities with new structures. Bioorg. Med. Chem. Lett. 2014, 24, 275.
4073−4079. (46) Brisbare-Roch, C.; Dingemanse, J.; Koberstein, R.; Hoever, P.;
(31) Porter, R. A.; Chan, W. N.; Coulton, S.; Johns, A.; Hadley, M. Aissaoui, H.; Flores, S.; Mueller, C.; Nayler, O.; van Gerven, J.; de
S.; Widdowson, D.; Jerman, J. C.; Brough, S. J.; Coldwell, M.; Smart, Haas, S. L.; Hess, P.; Qiu, C.; Buchmann, S.; Scherz, M.; Weller, T.;
D.; Jewitt, F.; Jeffrey, P.; Austin, N. 1,3-Biarylureas as selective non- Fischli, W.; Clozel, M.; Jenck, F. Promotion of sleep by targeting the
peptide antagonists of the orexin-1 receptor. Bioorg. Med. Chem. Lett. orexin system in rats, dogs, and humans. Nat. Med. 2007, 13, 150−155.
2001, 11, 1907−1910. (47) The sleep efficacy quoted in all figures is the minimum
(32) Smart, D.; Sabido-David, C.; Brough, S. J.; Jewitt, F.; Johns, A.; efficacious dose reported in the primary literature in all species. This
Porter, R. A.; Jerman, J. C. SB-334867: The first selective orexin-1 comparative method was selected due to the variety of methods
receptor antagonist. Br. J. Pharmacol. 2001, 132, 1179−1182. utilized to depict sleep efficacy in the literature.
(33) The convention of utilizing >20× selectivity as a determinant of (48) Uslaner, J. M.; Tye, S. J.; Eddins, D. M.; Wang, X.; Fox, S. V.;
DORA versus SORA profile was initiated to simplify the narrative Savitz, A. T.; Binns, J.; Cannon, C. E.; Garson, S. L.; Yao, L.; Hodgson,
within the field. This convention is not reflective of underlying R.; Stevens, J.; Bowlby, M. R.; Tannenbaum, P. L.; Brunner, J.;
pharmacology. Please see: Roecker, A. J.; Coleman, P. J. Orexin Mcdonald, T. P.; Gotter, A. L.; Kuduk, S. D.; Coleman, P. J.; Winrow,
receptor antagonists: Medicinal chemistry and therapeutic potential. C. J.; Renger, J. J. Orexin receptor antagonists differ from standard
Curr. Top. Med. Chem. 2008, 8, 977−987. sleep drugs by promoting sleep at doses that do not disrupt cognition.
(34) Duxon, M. S.; Stretton, J.; Starr, K.; Jones, D. N. C.; Holland, Sci. Transl. Med. 2013, 5, 179ra44.
V.; Riley, G.; Jerman, J.; Brough, S.; Smart, D.; Johns, A.; Chan, W.; (49) Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T.
Porter, R. A.; Upton, N. Evidence that orexin-A-evoked grooming in A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite
the rat is mediated by orexin-1 (OX1) receptors, with downstream 5- concept as applied in medicinal chemistry to mitigate the risk of
HT2C receptor involvement. Psychopharmacology 2001, 153, 203−209. idiosyncratic drug toxicitiy: A perspective based on the critical

527 DOI: 10.1021/acs.jmedchem.5b00832

J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

examination of trends in the top 200 drugs marketed in the United (63) Winrow, C. J.; Gotter, A. L.; Cox, C. D.; Doran, S. M.;
States. Chem. Res. Toxicol. 2011, 24, 1345−1410. Tannenbaum, P. L.; Breslin, M. J.; Garson, S. L.; Fox, S. V.; Harrell, C.
(50) Dingemanse, J.; Hoever, P.; Hoch, M.; Treiber, A.; Wagner- M.; Stevens, J.; Reiss, D. R.; Cui, D.; Coleman, P. J.; Renger, J. J.
Redeker, W.; Miraval, T.; Hopfgartner, G.; Shakeri-Nejad, K. Promotion of sleep by suvorexant − a novel dual orexin receptor
Elucidation of the metabolic pathways and the resulting multiple antagonist. J. Neurogenet. 2011, 25, 52−61.
metabolites of almorexant, a dual orexin receptor antagonist, in (64) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.;
humans. Drug Metab. Dispos. 2013, 41, 1046−1059. McGaughey, G. B.; Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.;
(51) Hoch, M.; van Gorsel, H.; van Gerven, J.; Dingemanse, J. Entry- Bednar, R. A.; Lemaire, W.; Bruno, J. G.; Reiss, D. R.; Harrell, C. M.;
into-humans study with ACT-462206, a novel dual orexin receptor Murphy, K. L.; Garson, S. L.; Doran, S. M.; Prueksaritanont, T.;
antagonist, comparing its pharmacodynamics with almorexant. J. Clin. Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T. D.; Cui, D.; Hartman,
Pharmacol. 2014, 54, 979−986. G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.;
(52) Boss, C.; Roch-Brisbare, C.; Steiner, M. A.; Treiber, A.; Dietrich, Coleman, P. J. Discovery of the dual orexin receptor antagonist [(7R)-
H.; Jenck, F.; von Raumer, M.; Sifferlen, T.; Brotschi, C.; Heidmann, 4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-meth-
B.; Williams, J. T.; Aissaoui, H.; Siegrist, R.; Gatfield, J. Structure- yl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the
activity relationship, biological, and pharmacological characterization treatment of insomnia. J. Med. Chem. 2010, 53, 5320−5332.
of the proline sulfonamide ACT-462206: A potent, brain-penetrant (65) McGaughey, G.; Bayly, C. I.; Cox, C. D.; Schreier, J. D.; Breslin,
dual orexin 1/orexin 2 receptor antagonist. ChemMedChem 2014, 9, M. J.; Bogusky, M. J.; Pitzenberger, S.; Ball, R.; Coleman, P. J. Shaping
2486−2496. suvorexant: Application of experimental and theoretical methods for
(53) Stachulski, A. V.; Baillie, T. A.; Park, B. K.; Obach, R. S.; Dalvie, driving synthetic designs. J. Comput.-Aided Mol. Des. 2014, 28, 5−12.
K.; Williams, D. P.; Srivastava, A.; Regan, S. L.; Antoine, D. J.; (66) Yin, J.; Mobarec, J. C.; Kolb, P.; Rosenbaum, D. M. Crystal
Goldring, C. E. P.; Chia, A. J. L.; Kitteringham, N. R.; Randle, L. E.; structure of the human OX2 orexin receptor bound to the insomnia
Callan, H.; Castrejon, J. L.; Farrell, J.; Naisbitt, D. J.; Lennard, M. S. drug suvorexant. Nature 2015, 519, 247−250 The PDB accession
The generation, detection, and effects of reactive drug metabolites. number for the crystal structure is 4RNB..
Med. Res. Rev. 2013, 33, 985−1080. (67) Winrow, C. J.; Gotter, A. L.; Cox, C. D.; Tannenbaum, P. L.;
(54) Di Fabio, R.; Pellacani, A.; Faedo, S.; Roth, A.; Piccoli, L.; Garson, S. L.; Doran, S. M.; Breslin, M. J.; Schreier, J. D.; Fox, S. V.;
Gerrard, P.; Porter, R. A.; Johnson, C. N.; Thewlis, K.; Donati, D.; Harrell, C. M.; Stevens, J.; Reiss, D. R.; Cui, D.; Coleman, P. J.;
Stasi, L.; Spada, S.; Stemp, G.; Nash, D.; Branch, C.; Kindon, L.; Renger, J. J. Pharmacological characterization of MK-6096 − A dual
Massagrande, M.; Poffe, A.; Braggio, S.; Chiarparin, E.; Marchioro, C.; orexin receptor antagonist for insomnia. Neuropharmacology 2012, 62,
Ratti, E.; Corsi, M. Discovery process and pharmacological character- 978−987.
ization of a novel dual orexin 1 and orexin 2 receptor antagonist useful (68) Coleman, P. J.; Schreier, J. D.; Cox, C. D.; Breslin, M. J.;
for treatment of sleep disorders. Bioorg. Med. Chem. Lett. 2011, 21, Whitman, D. B.; Bogusky, M. J.; McGaughey, G. B.; Bednar, R. A.;
5562−5567. Lemaire, W.; Doran, S. M.; Fox, S. V.; Garson, S. L.; Gotter, A. L.;
(55) Branch, C. L.; Johnson, C. N.; Stemp, G.; Thewlis, K. Harrell, C. M.; Reiss, D. R.; Cabalu, T. D.; Cui, D.; Prueksaritanont,
Preparation of piperidines as orexin receptor antagonists. WO T.; Stevens, J.; Tannenbaum, P. L.; Ball, R. G.; Stellabott, J.; Young, S.
2001096302, December 20, 2001. D.; Hartman, G. D.; Winrow, C. J.; Renger, J. J. Discovery of [2R,5R)-
(56) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the 5-{{(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-
structural diversity, substitution patterns, and frequency of nitrogen methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): A dual
heterocycles among U.S. FDA approved pharmaceuticals. J. Med. orexin receptor antagonists with potent sleep-promoting properties.
Chem. 2014, 57, 10257−10274. ChemMedChem 2012, 7, 415−424.
(57) Renzulli, C.; Nash, M.; Wright, M.; Thomas, S.; Zamuner, S.; (69) Steiner, M. A.; Gatfield, J.; Brisbare-Roch, C.; Dietrich, H.;
Pellegatti, M.; Bettica, P.; Boyle, G. Disposition and metabolism of Treiber, A.; Jenck, F.; Boss, C. Discovery and characterization of ACT-
[14C]SB-649868, and orexin 1 and 2 receptor antagonist, in humans. 335827, an orally available, brain penetrant orexin receptor type 1
Drug Met. Dispos. 2011, 39, 215−227. selective antagonist. ChemMedChem 2013, 8, 898−903.
(58) No active clinical investigations are available for SB-649868 on (70) Roecker, A. J.; Mercer, S. P.; Bergman, J. M.; Gilbert, K. F.; Search performed on May 22, 2015. Kuduk, S. D.; Harrell, C. M.; Garson, S. L.; Fox, S. V.; Gotter, A. L.;
(59) Coleman, P. J.; Cox, C. D.; Roecker, A. J. Discovery of dual Tannenbaum, P. L.; Prueksaritanont, T.; Cabalu, T. D.; Cui, D.;
orexin receptor antagonists (DORAs) for the treatment of insomnia. Lemaire, W.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Discovery of
Curr. Top. Med. Chem. 2011, 11, 696−725. diazepane amide DORAs and 2-SORAs enabled by exploration of
(60) Whitman, D. B.; Cox, C. D.; Breslin, M. J.; Brashear, K. M.; isosteric quinazoline replacements. Bioorg. Med. Chem. Lett. 2015,
Schreier, J. D.; Bogusky, M. J.; Bednar, R. A.; Lemaire, W.; Bruno, J. DOI: 10.1016/j.bmcl.2014.12.081.
G.; Hartman, G. D.; Reiss, D. R.; Harrell, C. M.; Kraus, R. L.; Li, Y.; (71) Raheem, I. T.; Breslin, M. J.; Bruno, J.; Cabalu, T. D.; Cooke, A.;
Garson, S. L.; Doran, S. M.; Prueksaritanont, T.; Li, C.; Winrow, C. J.; Cox, C. D.; Cui, D.; Garson, S.; Gotter, A. L.; Fox, S. V.; Harrell, C.
Koblan, K. S.; Renger, J. J.; Coleman, P. J. Discovery of a potent, CNS- M.; Kuduk, S. D.; Lemaire, W.; Prueksaritanont, T.; Renger, J. J.;
penetrant orexin receptor antagonist based on an N,N-disubstituted- Stump, C.; Tannenbaum, P. L.; Williams, P. D.; Winrow, C. D.;
1,4-diazepane scaffold that promotes sleep in rats. ChemMedChem Coleman, P. J. Discovery of piperidine ethers as selective orexin
2009, 4, 1069−1074. receptor antagonists (SORAs) inspired by filorexant. Bioorg. Med.
(61) Cox, C. D.; McGaughey, G. B.; Bogusky, M. J.; Whitman, D. B.; Chem. Lett. 2015, 25, 444−450.
Ball, R. G.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Conformational (72) Kuduk, S. D.; Skudlarek, J. W.; DiMarco, C. N.; Bruno, J. G.;
analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists Pausch, M. A.; O’Brien, J. A.; Cabalu, T. D.; Stevens, J.; Brunner, J.;
and implications for receptor binding. Bioorg. Med. Chem. Lett. 2009, Tannenbaum, P. L.; Garson, S. L.; Savitz, A. T.; Harrell, C. M.; Gotter,
19, 2997−3001. A. L.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Identification of MK-
(62) Coleman, P. J.; Schreier, J. D.; Roecker, A. J.; Mercer, S. P.; 8133: An orexin-2 selective receptor antagonist with suitable
McGaughey, G. B.; Cox, C. D.; Hartman, G. D.; Harrell, C. M.; Reiss, development properties. Bioorg. Med. Chem. Lett. 2015, 25, 2488−
D. R.; Doran, S. M.; Garson, S. L.; Anderson, W. B.; Tang, C.; 2492.
Prueksaritanont, T.; Winrow, C. J.; Renger, J. J. Discovery of 3,9- (73) Mercer, S. P.; Roecker, A. J.; Garson, S.; Reiss, D. R.; Harrell, C.
diazabicyclo[4.2.1]nonanes as potent dual orexin receptor antagonists M.; Murphy, K. L.; Bruno, J. G.; Bednar, R. A.; Lemaire, W.; Cui, D.;
with sleep-promoting activity in the rat. Bioorg. Med. Chem. Lett. 2010, Cabalu, T. D.; Tang, C.; Prueksaritanont, T.; Hartman, G. D.; Young,
20, 4201−4205. S. D.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Discovery of 2,5-

528 DOI: 10.1021/acs.jmedchem.5b00832

J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

diarylnicotinamides as selective orexin-2 receptor antagonists (2- (88) Herring, W. J.; Snyder, E.; Budd, K.; Hutzelmann, J.; Snavely,
SORAs). Bioorg. Med. Chem. Lett. 2013, 23, 6620−6624. D.; Liu, K.; Lines, C.; Roth, T.; Michelson, D. Orexin receptor
(74) Di, L.; Rong, H.; Feng, B. Demystifying brain penetration in antagonism for treatment of insomnia: A randomized clinical trial of
central nervous system drug discovery. J. Med. Chem. 2013, 56, 2−12. suvorexant. Neurology 2012, 79, 2265−2274.
(75) Roecker, A. J.; Mercer, S. P.; Schreier, J. D.; Cox, C. D.; Fraley, (89) Herring, W. J.; Connor, K. M.; Ivgy-May, N.; Snyder, E.; Liu, K.;
M. E.; Steen, J. T.; Lemaire, W.; Bruno, J. G.; Harrell, C. M.; Garson, Snavely, D. B.; Krystal, A. D.; Walsh, J. K.; Benca, R. M.; Rosenberg,
S. L.; Gotter, A. L.; Fox, S. V.; Stevens, J.; Tannenbaum, P. L.; R.; Sangal, R. B.; Budd, K.; Hutzelmann, J.; Leibensperger, H.;
Prueksaritanont, T.; Cabalu, T. D.; Cui, D.; Stellabott, J.; Hartman, G. Froman, S.; Lines, C.; Roth, T.; Michelson, D. Suvorexant in patients
D.; Young, S. D.; Winrow, C. J.; Renger, J. J.; Coleman, P. J. Discovery with insomnia: Results from two 3-month randomized controlled
of 5″-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2′:5′,3″-terpyr- clinical trials. Biol. Psychiatry 2014, 10.1016/j.biopsych.2014.10.003.
idine-3′-carboxamide (MK-1064): A selective orexin-2 receptor (90) Michelson, D.; Snyder, E.; Paradis, E.; Chengan-Liu, M.;
antagonist (2-SORA) for the treatment of insomnia. ChemMedChem Snavely, D. B.; Hutzelmann, J.; Walsh, J. K.; Krystal, A. D.; Benca, R.
2014, 9, 311−322. M.; Cohn, M.; Lines, C.; Roth, T.; Herring, W. J. Safety and efficacy of
(76) Roecker, A. J.; Reger, T. S.; Mattern, M. C.; Mercer, S. P.; suvorexant during 1-year treatment of insomnia with subsequent
Bergman, J. M.; Schreier, J. D.; Cube, R. V.; Cox, C. D.; Li, D.; abrupt treatment discontinuation: a phase 3 randomized, double-blind,
Lemaire, W.; Bruno, J. G.; Harrell, C. M.; Garson, S. L.; Gotter, A. L.; placebo-controlled trial. Lancet Neurol. 2014, 13, 461−471.
Fox, S. V.; Stevens, J.; Tannenbaum, P. L.; Prueksaritanont, T.; Cabalu, (91) FDA Approves New Type of Sleep Drug, Belsomra; U.S. Food and
T. D.; Cui, D.; Stellabott, J.; Hartman, G. D.; Young, S. D.; Winrow, C. Drug Administration: Silver Spring, MD, August 13, 2014; http://
J.; Renger, J. J.; Coleman, P. J. Discovery of MK-3697: A selective
orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. ucm409950.htm (accessed July 27, 2015).
Bioorg. Med. Chem. Lett. 2014, 24, 4884−4890. (92) Belsomra Highlights of Prescribing Information; Merck & Co.,
(77) Actelion and GSK Discontinue Clinical Development of Inc.: Whitehouse Station, NJ, 2014;
Almorexant; Actelion Pharmaceuticals Ltd.: Allschwil, Switzerland, product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf (accessed July
January 28, 2011; 27, 2015). (accessed July 27, 2015). (93) Sun, H.; Brown, K.; Calder, N.; Li, X.; Yee, K.; Perlstein, I.;
(78) Polysomnography study of MK6096 in patients with primary Wilbraham, D.; Rosen, L.; Chodakewitz, J.; Wagner, J.; Murphy, M. G.
insomnia (6096−011).; U.S. National Institutes of MK-6096, a dual orexin receptor antagonist, enhances sleep onset and
Health: Bethesda, MD, 2009; maintenance as measured by PSG in healthy male subjects. Sleep Biol.
results?term=MK-6096&Search=Search (accessed July 27, 2015). Rhythms 2011, 9, 334.
(79) Hoever, P.; de Haas, S.; Winkler, J.; Schoemaker, R. C.; Chiossi, (94) Search on MK-6096 .; U.S. National Institutes
of Health: Silver Spring, MD;
E.; van Gerven, J.; Dingemanse, J. Orexin receptor antagonism, a new
results?term=MK-6096&Search=Search (accessed July 27, 2015).
sleep-promoting paradigm: An ascending single-dose study with
(95) Chabi, A.; Zhang, Y.; Jackson, S.; Cady, R.; Lines, C.; Herring,
almorexant. Clin. Pharmacol. Ther. 2010, 87, 593−600.
W. J.; Connor, K. M.; Michelson, D. Randomized controlled trial of
(80) Hoever, P.; Dorffner, G.; Benes, H.; Penzel, T.; Danker-Hopfe,
the orexin receptor antagonist filorexant for migraine prophylaxis.
H.; Barbanoj, M. J.; Pillar, G.; Saletu, B.; Polo, O.; Kunz, D.; Zeitlhofer,
Cephalalgia 2015, 35, 379−388.
J.; Berg, S.; Partinen, M.; Bassetti, C. L.; Hogl, B.; Ebrahim, I. O.;
(96) Hoch, M.; van Gorsel, H.; van Gerven, J.; Dingemanse, J. Entry-
Holsboer-Trachsler, E.; Bengtsson, H.; Peker, Y.; Hemmeter, U.-M.; into-humans study with ACT-462206, a novel dual orexin receptor
Chiossi, E.; Hajak, G.; Dingemanse, J. Orexin receptor antagonism, a antagonist, comparing its pharmacodynamics with almorexant. J. Clin.
new sleep-enabling paradigm: A proof-of-concept clinical trial. Clin. Pharmacol. 2014, 54, 979−986.
Pharmacol. Ther. 2012, 91, 975−985. (97) Terauchi, T. Discovery of a novel and potent dual orexin 1/
(81) Actelion and GlaxoSmithKline Enter Into Exclusive Collaboration orexin 2 receptor antagonist, E2006, for the treatment of sleep
to Realise the Full Potential of Almorexant in Sleep Disorders and Beyond; disorders. 249th ACS National Meeting and Exposition, Denver, CO,, March 22−26, 2015, MEDI-24.
enter-into-exclusive-collaboration-realise-full-potential-almorexant- (98) This manuscript was published concomitant with the
sleep-8394.html (accessed July 27, 2015). submission of this perspective: Yoshida, Y.; Naoe, Y.; Terauchi, T.;
(82) The clinical development of almorexant was discontinued on Ozaki, F.; Doko, T.; Takemura, A.; Tanaka, T.; Sorimachi, K.;
January 28, 201 . Actelion and GSK Discontinue Clinical Development of Beuckmann, C. T.; Suzuki, M.; Ueno, T.; Ozaki, S.; Yonaga, M.
Almorexant; Actelion Pharmaceuticals, Ltd.: Allschwil, January 28, Discovery of (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-
2011; (3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide
page?newsId=1483135 (accessed July 27, 2015). (E2006): A potent and efficacious oral orexin receptor antagonist. J.
(83) SB649868 . ClinicalTrials.go; U.S. National Institutes of Health: Med. Chem. 2015, 58, 4648−4664.
Bethesda, MD; (99) Coleman, P. J.; Cox, C. D.; Breslin, M. J.; Schreier, J. D.;
SB649868&Search=Search (accessed July 27, 2015). Roecker, A. J.; Whitman, D. B.; Mercer, S. M.; Tannenbaum, P. L.;
(84) Bettica, P.; Nucci, G.; Pyke, C.; Squassante, L.; Zamuner, S.; Gotter, A. L.; Garson, S. L.; Fox, S. V.; Harrell, C. M.; Stevens, J.;
Ratti, E.; Gomeni, R.; Alexander, R. Phase I studies on the safety, Doran, S. M.; Reiss, D. R.; Lemaire, W.; Bruno, J. J.; Cabalu, T. D.;
tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a Cui, D.; Prueksaritanont, T.; Young, S. D.; Hartman, G. D.; Winrow,
novel dual orexin receptor antagonist. J. Psychopharmacol. 2012, 26, C. J.; Renger, J. J. Discovery and characterization of OX2R/OX1R and
1058−1070. OX2R antagonists for the treatment of sleep disorders. 248th ACS
(85) Bettica, P.; Squassante, L.; Zamuner, S.; Nucci, G.; Danker- National Meeting and Exposition, San Francisco, CA, August 10−14,
Hopfe, H.; Ratti, E. The orexin antagonist SB-649868 promotes and 2014, MEDI-334.
maintains sleep in men with primary insomnia. Sleep 2012, 8, 1097− (100) Preclinical DORA/2-SORA efficacy differentiation remains a
1104. controversial topic. For details on the controversy, see: (a) Moriarty, S.
(86) Ratti, E. GlaxoSmithKline: Investor Update . 2007. R.; Revel, F. G.; Malherbe, P.; Moreau, J.-L.; Valladao, D.; Wettstein, J.
(87) Sun, H.; Kennedy, W. P.; Wilbraham, D.; Lewis, N.; Calder, N.; G.; Kilduff, T. S.; Borroni, E. Dual hypocretin receptor antagonism is
Li, X.; Ma, J.; Yee, K. L.; Ermlich, S.; Mangin, E.; Lines, C.; Rosen, L.; more effective for sleep promotion than antagonism of either receptor
Chodakewitz, J.; Murphy, G. M. Effects of suvorexant, an orexin alone. PLoS One 2012, 7, e39131. (b) Dugovic, C.; Shelton, J. E.; Yun,
receptor antagonist, on sleep parameters measured by polysomnog- S.; Bonaventure, P.; Shireman, B. T.; Lovenberg, T. W. Orexin-1
raphy in healthy men. Sleep 2013, 36, 259−267. receptor blockade dysregulates REM sleep in the presence of orexin-2

529 DOI: 10.1021/acs.jmedchem.5b00832

J. Med. Chem. 2016, 59, 504−530
Journal of Medicinal Chemistry Perspective

receptor antagonism. Front. Neurosci. 2014, 8, doi: 10.3389/

(101) (a) Letavic, M. A.; Bonaventure, P.; Ly, K. S.; Aguilar, Z.;
Aluisio, L.; Carruthers, N. I.; Chaplan, S.; Dugovic, C.; Halter, R.;
Kudriakova, T.; Lord, B.; Lovenberg, T. W.; Kramer, M.; Morton, K.
L.; Ndifor, A.; Rizzolio, M.; Shah, C.; Shelton, J. Shoblock, J.; Sutton,
S. Discovery of JNJ-42847922, a selective orexin-2 antagonist for the
treatment of insomnia disorder. 249th ACS National Meeting and
Exposition, Denver, CO, March 22−26, 2015, MEDI-244. (b) This
manuscript was published concomitant with the submission of this
perspective: Letavic, M. A.; Bonaventure, P.; Carruthers, N. I.;
Dugovic, C.; Koudriakova, T.; Lord, B.; Lovenberg, T. W.; Ly, K. S.;
Mani, N. S.; Nepomuceno, D.; Pippel, D. J.; Rizzolio, M.; Shelton, J.
E.; Shah, C. R.; Shireman, B. T.; Young, L. K.; Yun, S. Novel
octahydropyrrolo[3,4-c]pyrroles are selective orexin-2 antagonists:
SAR leading to a clinical candidate. J. Med. Chem. 2015, 58, 5620−
(102) Result of a Scifinder search for “orexin antagonists” limiting by
patent literature and public disclosures of clinical candidates in March
(103) Belsomra (suvorexant) was approved for the treatment of
insomnia by the FDA on August 13, 2014.
(104) Human genetics has been forwarded recently as a strong target
validation approach to drug discovery: Plenge, R. M.; Scolnick, E. M.;
Altshuler, D. Validating therapeutic targets through human genetics.
Nat. Rev. Drug Discovery 2013, 12, 581−594.
(105) Both GSK (reference 54) and Eisai DORA efforts have
described the use of a U-shaped conformation in compound design
after initial reports from Merck. For the Eisai effort, see: Yoshida, Y.;
Terauchi, T.; Naoe, Y.; Kazuta, Y.; Ozaki, F.; Beuckmann, C.;
Nakagawa, M.; Suzuki, M.; Kushida, I.; Takenaka, O.; Ueno, T.;
Yonaga, M. Design, synthesis, and structure-activity relationships of a
series of novel N-aryl-2-phenylcyclopropane carboxamide that are
potent and orally active orexin receptor antagonists. Bioorg. Med.
Chem. 2014, 22, 6071−6088.
(106) Christopher, J. A.; Aves, S.; Brown, J.; Errey, J.; Klair, S.;
Langmead, C.; Mace, O.; Mould, R.; Patel, J.; Tehan, B.; Zhukov, A.;
Marshall, F.; Congreve, M. Discovery of 2-(5,6-dimethoxypyridin-3-
1,1-dioxide (HTL6641), a dual orexin receptor antagonist with
differentiated pharmacodynamic properties. MedChemComm 2015, 6,
(107) Fujimoto, T.; Kunitomo, J.; Tomata, Y.; Nishiyama, K.;
Nakashima, M.; Hirozane, M.; Yoshikubo, S.-I.; Hirai, K.; Marui, S.
Discovery of potent, selective, orally active benzoxazepine-based
orexin-2 receptor antagonists. Bioorg. Med. Chem. Lett. 2011, 21,
(108) Suzuki, R.; Nozawa, D.; Futamura, A.; Nishikawa-Shimono, R.;
Abe, M.; Hattori, N.; Ohta, H.; Araki, Y.; Kambe, D.; Ohmichi, M.;
Tokura, S.; Aoki, T.; Ohtake, N.; Kawamoto, H. Discovery and in vitro
and in vivo profiles of N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-
pyrazol-1yl]ethyl]-2-(2H-1,2,3-triazol-2yl)-benzamide as a novel class
of dual orexin receptor antagonist. Bioorg. Med. Chem. 2015, 23,
(109) Uslaner, J. M.; Winrow, C. J.; Gotter, A. L.; Roecker, A. J.;
Coleman, P. J.; Hutson, P. H.; Li, A. D.; Renger, J. J. Selective orexin 2
receptor antagonism blocks cue-induced reinstatement, but not
nicotine self-administration or nicotine-induced reinstatement. Behav.
Brain Res. 2014, 269, 61−65.
(110) During the preparation of this Perspective, a manuscript
detailing the discovery of small molecule orexin agonists was
published: Nagahara, T.; Saitoh, T.; Kutsumura, N.; Irukayama-
Tomobe, Y.; Ogawa, Y.; Kuroda, D.; Gouda, H.; Kumagai, H.; Fujii,
H.; Yanagisawa, M.; Nagase, H. Design and synthesis of non-peptide,
selective orexin receptor 2 agonists. J. Med. Chem. 2015,
DOI: 10.1021/acs.jmedchem.5b00988.

530 DOI: 10.1021/acs.jmedchem.5b00832

J. Med. Chem. 2016, 59, 504−530