Lead Optimization in Drug Discovery/DMPK

Case Study : Hepatitis C virus Protease Inhibitor SCH

503034
Abstract: Lead Optimization and drug metabolism and pharmacokinetics(DMPK) has become primary
focuses of research involved in drug discovery. Using in vivo and in vitro DMPK screening, a
large array of compounds during LO process has resulted in development of compounds that have
acceptable DMPK properties. In this poster I present a general drug discovery process and a
case study using HCV protease inhibitor as an example.

Introduction: Lead Generation as a part of new drug

•Multifaceted Operation
•Involves interaction between DMPK scientist,
biologist and physical chemists.
•Goal: to find molecule with desired
Biological Activity, DMPK property and safety
Drug Metabolism As a Part of New Drug
Discovery:
Scheme shows: Nature of Property
lead optimization leading
to candidate
•DMPK provides with tools Duration (Half-life)
discovery:
•Contemporary parallel and combinatorial
chemical synthesis produce large arrays of
compounds
•Improvements by structural chemist using
variety of tools, e.g. X-ray crystallography,
High throughput binding targets
•New automated in vitro Screening –can test
100’s of sample in short time.
•Increase our ability to create New Chemical
Entity(NCE)
Lead optimization in a DMPK environment
Potency
Definition/Requirement
The intrinsic ability of a compound to produce a desirable
pharmacological response (usually measured via high throughput in vitro
screens)
Oral Bioavailability The ability of a compound to pass through multiples barriers, such as the
GI tract and the liver in order to reach the target
The ability of the compound to remain in circulation (or at the target site)

and the assay to assess Safety

for sufficient time to provide a meaningful pharmacological response

various NCE in terms of

The compound has sufficient selectivity for the targeted response relative
to non-targeted responses so that an adequate therapeutic index exists

ADME and pharmacokinetic Pharmaceutical Acceptability The compound has suitable pharmaceutical properties, such as a

parameters
reasonable synthetic pathway, adequate aqueous solubility, reasonable rate
of dissolution, good chemical stability, etc.

•Goal is to find a
compound suitable for
development

Case study: HCV protease Screening Paradigm Result-

Hepatitis C virus Method
: : •moderate oral bioavailability in rats and dogs
•~170 million people infected with •Absence of reactive metabolite
HCV •IC50>5uM for CYPs3A4, 2D6, 2C8 and 2C9
•Chronic form of hepatitis •Moderate huan Hepatocyte clearance
•HCV servers a template for cap •No CYP induction liability
independent translation through its
5’ terminal.
•3000amino acid undergo-co and post
translational proteolytic maturation
by host and virus. Macrocyclic Compounds: SCH
•Virus encoded protease located at 416538, resistance to peptidases
NS3. and amidases, Better potency.
•This effect targeting the E-S Secondary Amides: SCH
binding site resulted in SCH 503034 446211,reasonable half life,
DMPK screening :
Level 1 DMPK screening applied to
Screens – Caco2 permeability
potential dosage regimen.
Primary Ketoamides: SCH 503034
Screen , Human hepatocyte Clearance
Screening , CYP enzyme inhibition screen ,
HCV compound ~ METHOD
hPXR screen , Esterase / amidase stability
screen , Rat liver uptake screen ,
Cassette - Accelerated Rapid rat screen
•10,000compounds --- Replicon met criteria for this program and
assay was advanced into development.
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•1,000 met the criterion of
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•1st level--- Screening with
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Caco2,CYP enzyme inhibition,

– in
Conclusion: DMPK screens and new techniques have
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liver uptake screening

re Do at at
Sc ng y, R , R key t
si ke on on Ra
become an essential part of drug discovery process.
Le
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ri mon cti , M nd
u D a
gl and ind e I ID, • There is continuous need to improve predictions by
Si at me lit te e
R nzy bo li anc using in vitro evaluations.
e eta bo al
m eta b
m ass
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•2nd level---More labor
intensive assay, studies in Future: It may become possible to use in silico DMPK
H 4
SC 03
rodent and non rodent computer model parameters to support the rapid
species.
3
50
screening of drugs to shorten the time frame of lead
optimization.
•Out of 1000, 3 were advanced
leads with SCH503034 Reference:
•A few advanced leads were identified that had •K.-C. Cheng1, Walter A. Korfmacher1, Ronald E. White1
acceptable DMPK characteristics. and F. George Njoroge2
• 1Department of Drug Metabolism and Pharmacokinetics .
2Chemistry Department Schering-Plough
•It went through a DMPK profiling process for the Research Institute, 2015 Galloping Hill Road,
final selection of the best compound for drug Kenilworth, NJ 07033 USA.
development (3rd level).