Prodrugs

• Definition:
• A pharmacologically inactive chemical entity that
when metabolized or chemically transformed by a
mammalian
system is converted into a pharmacologically active
substance

• Why use prodrugs?

– Improve patient acceptability (decrease pain on
injection)
– Alter and improve absorption
– Alter biodistribution
– Alter metabolism
– Alter elimination
 Types of Prodrugs
• I. Carrier-linked prodrug
• A compound that contains an active drug linked
to a carrier group that is removed enzymatically
• II. Bioprecursor prodrug
• metabolized into a new compound that
may itself be active or further metabolized
to an active metabolite (e.g. amine to
aldehyde to carboxylic acid).
 Carrier-linked prodrug

• Carrier-linked prodrugs can be further

subdivided into
• A. bipartate - comprised of one carrier
attached to drug
• B. tripartate - carrier connected to a linker
that is connected to drug
• C. mutual - two, usually synergistic, drugs
attached to each other
 EX FOR CARRIER LINKED
BIPARTATE PRODRUGS
• Prodrugs for increased water solubility
• Prodrugs for improved absorption &
distribution
• Prodrugs for site specificity
• Prodrugs for stability
Prodrugs for increased solubility
• Artemisinin is an antimalarial drug that is
insoluble in water. Their succinic acid
ester derivative artesunate is water soluble
and can be used for parenteral use.

Artemisinin
Artesunate
 Chloramphenicol
Chloramphenicol

OH Cl
H
N
Cl
OH Cl
H O
N Esterase O2 N O
Cl H
O
O2 N O
O-Na+ or Water
O OH
O O-Na+
O
O
Chloramphenicol Succinate
Sodium succinate
• Enzymatic and intramolecular spontaneous hydrolysis
• Increased water solubility, ester itself is inactive as an antibiotic
• Promoiety should be nontoxic and easily excreted
• Type of promoiety chosen is a function of properties desired
 Prodrug for improved absorption
and distribution
• Arbaclofen placarbil is a novel transported prodrug of the pharmacologically
active R-isomer of baclofen
• Baclofen is a racemic GABA(B) receptor agonist 
• This conversion seems to be primarily catalyzed in human tissues by human
carboxylesterase-2, a major carboxylesterase expressed at high levels in
various tissues including human intestinal cells.
• Baclofen is used for treating spasm of skeletal muscles.

carboxylesterase-2

Arbaclofen placarbil (R)-Baclofen

 OR
O
CH3 CH3
HO O
CH3
CH3 O

F
O
F
fluocinolone acetonide (R = H)
fluocinonide (R = COCH 3 )
8.14

corticosteroids - inflammation,
allergic, pruritic skin
conditions
• Prodrugs for Improved Absorption and Distribution

• Dipivefrin is a prodrug for the antiglaucoma drug

epinephrine.The dipivaloyl esters allow for greater corneal
permeability which are hydrolyzed by corneal and aqueous
humor esterases.
 Prodrug for Site specificity
• The blood-brain barrier prevents hydrophilic molecules from
entering the brain, unless actively transported. The anticonvulsant
drug vigabatrin crosses poorly. A glyceryllipid (R = linolenoyl)
containing one GABA ester and one vigabatrinester was 300 times
more potent in vivo than vigabatrin.

Vigabatrin
 Prodrug for Site specificity
• Oxyphenisatin is a bowel stimulant and is only active
when administered rectally.
• Acetylation (protection) of the hydroxyls allow the drug to
be administered orally which is then hydrolysed at the
desired site of action, the intestines.

Oxyphenisatin
Oxyphenisatin acetate
Prodrugs for Site Specificity.
Oxyphenisatin is a bowel sterilant that is only active when
administered rectally. Acetylation (protection) of the
hydroxyls allow the drug to be administered orally which is
then hydrolyzed at the desired site of action, the intestines.
Prodrugs for Stability
Prodrugs may protect a drug from 1st-pass effects.
Propranolol (antihypertensive drug) suffers from first-pass elimination resulting
in decreased bioavailability of oral doses compared to i.v. injections. One of the
major metabolites is the O-glucuronide. The hemisuccinate ester was designed to
block glucuronide formation resulting in an 8-fold increase of plasma levels of
propranolol.
 Prodrug for Stability
protection from first-pass effect
Oral administration has lower bioavailability than i.v. injection.

O NHCH(CH3 )2
OR'

R
propanolol (R = R' = H)
8.22
antihypertension
O
prodrug R' = CCH2 CH2COOH
plasma levels 8 times that with propanolol
 Prodrugs to Minimize Toxicity

Many of the prodrugs just discussed also have lowered toxicity.

For example, epinephrine (for glaucoma) has ocular and systemic side effects
not found in dipivaloylepinephrine.
 Prodrug to Increase Patient
AcceptanceCH 3
The antibacterial drug clindamycin H
N H
(8.28) is bitter and not well tolerated
N Cl
by children.
Clindamycin palmitate is not bitter. O HO O
H
OH
SCH3
OR
clindomycin (R = H)
clindomycin phosphate (R = PO 3H 2)
clindomycin palmitate (R = O(CH 2) 14 CH3 )
8.28
Either not soluble in saliva or does not bind to the bitter taste receptor or both.
 Prodrug to Eliminate Formulation
Problems
Formaldehyde is a gas with a pungent odor that is
used as a disinfectant. Too toxic for direct use.
N

H+
CH2O + NH3 N N
H3O+ N

methenamine
8.30
It is a stable solid that decomposes in aqueous acid.
The pH of urine in the bladder is about 4.8, so
methenamine is used as a urinary tract antiseptic.
Has to be enteric coated to prevent hydrolysis in the
 Tripartate Drugs
(Self-immolative Prodrugs)
A bipartate prodrug may be ineffective because
the linkage is too labile or too stable.
In a tripartate prodrug, the carrier is not
attached to the drug; rather, to the linker.
Therefore, more flexibility in the types of
functional groups and linkages that can be
used, and it moves the cleavage site away from
the carrier.
The linker-drug bond must cleave
spontaneously (i.e., be self-immolative) after
the carrier-linker bond is broken.
 Tripartate Prodrugs
Scheme 8.8

enzyme
Carrier Linker Drug Carrier + Linker Drug

spontaneous

Linker + Drug
 Tripartate Prodrugs of Ampicillin
O

Poor oral absorption (40%) NH

S
NH2
Excess antibiotic may
N
destroy important intestinal O
bacteria used in digestion COO-
ampicillin
and for biosynthesis of 8.44
cofactors. antibacterial
Also, more rapid onset of
resistance.
Various esters made were too stable in humans
(although they were hydrolyzed in rodents) - thought
the thiazolidine ring sterically hindered the esterase.
 Tripartate Prodrugs of Ampicillin
Scheme 8.10
O O
Ph Ph
NH NH
S S
NH 2 esterase NH2
+ R'COOH
N N
O O ..
O O R' O OH when
O O R' = OEt
R O R
8.46
bacampicillin (R = CH 3 , R' = OEt) EtOH
pivampicillin (R = H, R' = t-Bu) O + CO2
8.45
R H

98-99% absorbed 8.44

Ampicillin is released in < 15 minutes
 Mutual Prodrugs
A bipartate or tripartate prodrug in which the carrier
is a synergistic drug with the drug to which it is
linked.
Antibacteria -lactamase inactivator
l ampicillin penicillanic acid sulfone
O
Ph
N O O
H S
NH 2 S
N
O O O N
O O O

sultamicillin
8.59
Hydrolysis gives 1:1:1 ampicillin : penicillanic acid
sulfone : formaldehyde
 Ideal Mutual Prodrugs
• Well absorbed
• Both components are released together
and quantitatively after absorption
• Maximal effect of the combination of the
two drugs occurs at 1:1 ratio
• Distribution/elimination of components are
similar
 Bioprecursor Prodrugs
Carrier-linked prodrugs largely use hydrolytic
activation
Bioprecursor drugs mostly use oxidative or
reductive activation

The metabolically-activated alkylating agents

discussed in Chapter 6 are actually examples of
bioprecursor prodrugs.
 Oxidative Activation
N-Dealkylation
Sedative 8.20

CH3 CH3 CH3

N N N

N N N N N
N
CH3 P450 CH 3 P450 NH
.. 2
O N N O
Cl O
CH3 Cl H Cl
X X X

CH3 N CH3 N
N
N N
-H2 O N

Cl N ..
Cl NH
HO X
X

alprazoalam (X = H)
triazolam (X = Cl)
8.77
 O-Dealkylation
Analgesic activity of phenacetin is a result
of O-dealkylation to acetaminophen.
O

HN CH3

OR
phenacetin (R = CH 2 CH3 )
acetaminophen (R = H)
8.78
 N-Oxidation
Pralidoxime chloride is an antidote for nerve
poisons.
It reacts with acetylcholinesterase that has been
inactivated by organophosphorus toxins.

N OH
+N
Cl -
CH3

pralidoxime chloride
8.91
 To increase the permeability of pralidoxime
into the CNS, the pyridinium ring was reduced
(8.92). N
N OH
CH3
8.92

oxidation into brain

N OH
-
+N
Cl
CH3
pralidoxime chloride
8.91
Similar to the reversible redox drug delivery strategy for getting
drugs into the brain by attaching them to a dihydronicotinic acid,
hydrophobic 8.92 crosses the blood-brain barrier; oxidation to
8.91 prevents efflux from brain.
 Reductive Activation
Azo Reduction
Scheme 8.29
COOH

NHSO2 N=N OH Anaerobic

N
sulfasalazine
cleavage by
8.106 bacteria in lower
ulcerative colitis COOH
bowel
H 2N OH + NHSO 2 NH2
N

8.107 sulfapyridine
8.108
For inflammatory Causes side
bowel disease effects
 To prevent side effect by sulfapyridine a macromolecular
delivery system was developed.

n poly(vinylamine)
NH
SO 2
Not absorbed or
metabolized in
spacer CO2Na
small intestine.
N N OH

8.109
CO 2Na

NH2 OH
Released by reduction at the disease
site.
Sulfapyridine is not released (still attached to polymer).
More potent than sulfasalazine.
 Sulfoxide Reduction
CO2H
F
CH3

CH 3 S
O
sulindac
8.111
anti-arthritis
Sulindac is inactive in vitro; the sulfide is active in vitro and in vivo.
Sulindac is an indane isostere of indomethacin, which was
designed as a serotonin analog.
The 5-F replaced the 5-OMe group to increase analgesic
properties.
The p-SOCH3 group replaced p-Cl to increase water solubility.
CO2H CO2H
F MeO
CH3 CH3
N NH2

O HO

CH3 S N
Cl H
O
indomethacin serotonin
sulindac 8.112
8.111
 Disulfide Reduction
To increase the lipophilicity of thiamin for absorption
into the CNS.
OH OH
Scheme 8.30 ..
N GSH N
N S S O N S-
O H O H
CH 3 N NH 2 CH3 N NH2
+B H
8.113

nonenzymatic

OH
+ N:
N N OH N S
S
CH3 N NH2 CH3 N NH2 OH

thiamin
8.114
poorly absorbed into CNS
 Nucleotide Activation
Scheme 8.33
=O
SH
3PO O O O
SH N N
O—P—O—P—O-
N N N N
HO OH O- O- =O
3PO O
N N
hypoxanthine-guanine
H phosphoribosyltransferase
6-mercaptopurine HO OH
8.122
Anti-leukemia drug 8.123
Inhibits several enzymes
in the purine nucleotide
biosynthesis pathway.
 Phosphorylation Activation
O
O N
HN
HN N
H 2N N N
H 2N N N HO
RO O
O
HO
acyclovir (R = H)
8.124 8.125
antiviral 2-deoxyguanosine
Resembles structure of 2-deoxyguanosine
viral thymidine kinase
Uninfected cells do R = PO3=
not phosphorylate viral guanylate kinase
acyclovir (selective R = P2O6-3
toxicity)
viral phosphoglycerate kinase
R = P3O9-4