Prodrugs of Functional Groups

!  Carboxylic acids and alcohols: Most common

!  Amines and azo linkages: Not been used much
!  Carbonyl compounds: Not found to be used widely
 Carboxylic Acids and Alcohols

Converted to ester prodrugs which are often hydrolyzed to active drug by different types of
esterase enzymes:

Ester hydrolase O O
Lipase
Drug O Promoiety Drug OH + HO Promoiety
Cholesterol esterase
Acetylcholinesterase or Esterase
Carboxypeptidase
O O
Cholinesterase Drug O Promoiety Drug OH + HO Promoiety
Microflora in the gut

Manipulation of steric and electronic properties of promoiety allows control of rate and
extent of hydrolysis
Advantage of Prodrug Formation I: Increased absorption of hydrophilic drugs by
making less hydrophilic or more lipophilic

CH3
H3C CH3
OH H OH H
O O NH+ HO NH+
CH3 Esterase CH3

O HO
O Epineprine
CH3
H3C CH3 H3C CH3
CH3

Dipivefrin O OH
Pivalic Acid

Prodrug of Epinephrine: Dipivefrin

!  More lipophilic, thus achieve higher intraocular concentration

!  Hydrolysis occur in cornea, conjunctiva, and aqueous humor after
ophthalmic application
Advantage of Prodrug Formation II: Masking unpleasant taste

Chloramphenicol palmitate and Clindamycin palmitate has already been shown.

Other drugs include

CH3 O
CH3 H C
N O
3 O
O H N CH3
O O CH3 O
H3C OH O
S HO O CH3
N O
H3 C
CH3 HO

H2N O CH3 H3C CH3

CH3
O O O
N-Acetyl sulfisoxazole CH3
CH3 CH3
O O OH CH3
CH3

Erythromycin estolate
O
CH3 H3 C
O
O O N CH3
H3C O
O O O CH3
H3C
H3 C

H3C CH3
H3C CH3
O O O
CH3 CH3
O O
O
CH3
O
Troleandomycin
Not all carboxylic esters hydrolyzed in vivo where double ester approach is used

H
R1 N
S CH3
Esterase
O No Reaction
N CH3
O
COOR2
(R2 = Ethyl, Propyl, Butyl, Phenyl)
Penicillin Esters
H
R1 N S
Esterase
O No Reaction
N R3
O
COOR2
(R2 = Ethyl, Propyl, Butyl, Phenyl)
Cephalosporin Esters
 OCH3
N H
N
H2N N S
S O
N OCH3
O CH3 O CH3
O O O O
Cefpodoxime Proxetil CH3
(Prodrug) CH3

Esterase
OCH3
N H
N
H2N N S
S O
N OCH3
O CH3 CH3
O O O H + CO2 + HO
CH3
CH3

OCH3
N H
N
H2N N S
S O
N OCH3 H3C
O O
+
O OH H3C
Advantage of prodrug formation III: Increase hydrophilicity and thus water solubility
to apply parenterally or also orally when compounds are too lipophilic to formulate in
liquid dosage form
O O O O

Drug O C C O-Na+ Drug OH + HO C C O-Na+

H2 H2 H2 H2
Succinates

O O

Drug O P O-Na+ Drug OH + HO P O-Na+

OH OH
Phosphates
O O

-
O
Drug OH + O

Drug O

O O

Rapid and thus the prodrug is unstable

 H CH3 H H2O H3PO4 CH3
CH3 CH3
N N H
N N
H3 C Cl H3C Cl
O OH Phosphatase
O OH
O O
HO HO
O OH
S CH3 S
O P OH Clindamycin CH3
O-
Clindamycin Phosphate
 Chemical Delivery System

The site specific delivery of drugs is an important way of increasing

drug
s therapeutic index. The knowledge of prodrug and drug
metabolism is used to concentrate drugs at its target site thus
minimizing the systemic toxicity.
HO

HO CH2CH COOH

NH2

BBB; Active transport to CNS

by L-Amino acid delivery system

HO HO

HO CH2CH COOH HO CH2CH2NH2

NH2
Dopamine (Active)
L-Dopa
Antedrugs (Soft Drugs)

I stopped taking medicine

as I prefer original disease
to side effects
!!

Because,
Vioxx
ll treat pain
but who
ll treat
vioxx
??
 Safety-Based Drug Withdrawals
from U.S. Market (2006-2007)

Drugs Therapeutic activity Date Date Primary health risk

approved withdrawn
Vioxx Antiinflammatory 05/99 09/04 Myocardial Infarction etc.
(Rofecoxib) (COX-2 inhibitor)

Ximelagatran Anticoagulant 2006 Hepatotoxicity

(Exanta)

Te g a s e r o d IBS, constipation 2002 2007 Cardiovascular ischemic

(Zelnorm) events
Aprotinin Induce bleeding 1960s 2007 Ischemic colitis and Severe
(Trasylol) during sergery) constipation
 Why the Adverse Drug Reactions Occur?

"  Because of unintended systemic actions in most

therapeutic classes of drugs

To bring a drug from concept to market

!  It takes about 10-15 years

!  $897 millions to $1.7 billions
!  Overall attrition rate 10,000:1
 What is Antedrug?

An active synthetic drug which is inactivated by a metabolic

process upon entry into the systemic circulation.
Therefore, a true antedrug acts only locally.

True Antedrug Inactive Metabolite

Partial Antedrug Less active metabolite

Lee HJ and Soliman MRI (1982). Science, 215, 989.

 OCOR OH

O O

OH OH
OH
IA A
Prodrug
O
OH OH OH
OH

O O

OH OH
Antedrug
O A CO 2R IA CO 2-
Hydrocortisone

(IA = Inactive Compound, A = Active Compound)

 Chemical Approaches

1)  The Carboxylic Esters and Amides

2)  20-Thioester Derivatives

3)  γ-Butyrolactone Derivatives

O CO2R O COOH
CH3 CH3
HO OH HO OH
CH3 H hydrolysis in plasma CH3 H

H H H H
O O

Stable locally and active Inactive

Inactivation of Steroid 21-ate Esters in Bood Plasma.

 O O O
CH3 OCOCH3 CH3 OH CH3 OH
HO OH HO OH HO OH
CH3 H CO2Me CH3 H CO2Me CH3 H COOH
t1/2 6.3 min t1/2 90 min
F H plasma F H plasma F H
O O O

O O OH
SCH2F
CH3 CH3
HO OCOEt HO OCOEt
CH3 H Me CH3 H Me
Liver
F H F H
O O
F F
Inactivation of Fluticasone Propianate Inactive
 Advantages of Antedrugs

!  Localization of the drug effects

!  Elimination of toxic metabolites, increasing the therapeutic index
!  Avoidance of pharmacologically active metabolites that can lead
to long-term effects
!  Elimination of drug interactions resulting from metabolite
inhibition of enzymes
!  Simplification of PK problems caused by multiple active species

M.O.F.Khan*, K.K.Park, H.J.Lee. Antedrugs: An Approach to Safer Drugs. Curr. Med. Chem., 12(19),
2227-2239, 2005.
 Phase II: Drug Conjugation

!  Attachment of small polar endogenous molecules such as

glucuronic acid, sulfate and amino acids to Phase I metabolites or
parent drugs
!  Products are more water-soluble and easily excretable
!  Attenuate pharmacological activity and thus toxicity
!  Trapping highly electrophilic molecules with endogenous
nucleophiles such as glutathione prevent damage to important
macromolecules (DNA, RNA, proteins)
!  Regarded as true detoxifying pathway (with few exceptions)
!  In general, appropriate transferase enzymes activate the
transferring group (glucuronate, sulphate, methyl, acetyl) in a
coenzyme form
 Glucuronic Acid Conjugation
!  Glucuronidation is the most common conjugation pathway
! The coenzyme, UDP glucuronic acid is synthesized from the corresponding
phosphate
! UDP-glucuronic acid contains D-glucuronic acid in the α-configuration at
the anomeric center, but glucuronate conjugates are β-glycoside, meaning
inversion of stereochemistry is involved in the glucuronidation
! Glucuronides are highly hydrophilic and water soluble
! UDP glucuronosyltransferase is closely associated with Cyp450 so that
Phase I products of drugs are efficiently conjugated
! Four general classes of glucuronides: O-, N-, S-, and C-
! Neonates have undeveloped liver UDP-glucuronosyltransferase activity,
and may exhibit metabolic problem. For example, chloramphenicol
(Chloroptic) leads neonates to “gray baby syndrome”
! Neonatal jaundice may be attributable to their inability to conjugate bilirubin
with glucuronic acid
 Formation of Glucuronide Conjugate
UTP PPi
HO HO O
HO O HO O
HO HO O O
Phosphorylase NH
HO HO
OPO 32- O P O P O
N O
α-D-Glucose-1- O- O- O +
phosphate 2NAD

U 2N
D
UDPG HO OH PG A
DH
de
hy
dr
og
en
as
e
HOOC O
HO O
HO O O NH
HO
O P O P O
N O
O- O- O

UDP-Glucuronyl-transferase
(microsomal)
OH HO
O RXH
HO Uridine-5'-diphospho-
HO O UDP α-D-Glucose (UDPG)
HO XR
HO
β-D-Glucuronide