DM pp61-80
DM pp61-80
DM pp61-80
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
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
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
O O
-
O
Drug OH + O
Drug O
O O
HO CH2CH COOH
NH2
HO HO
NH2
Dopamine (Active)
L-Dopa
Antedrugs (Soft Drugs)
Because,
Vioxxll treat pain
but wholl treat
vioxx
??
Safety-Based Drug Withdrawals
from U.S. Market (2006-2007)
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
O CO2R O COOH
CH3 CH3
HO OH HO OH
CH3 H hydrolysis in plasma CH3 H
H H H H
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
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
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