The document discusses various prodrugs, their mechanisms, and applications, such as estermustine for prostate cancer and erythromycin for infections. It details the hydrolysis processes mediated by different types of enzymes and the significance of promoieties in enhancing pharmacokinetics. Specific examples illustrate the challenges faced by certain prodrugs, including their stability and absorption improvements.

1. Mutual Prodrug
Actual alkylating species
CH3
OH
OH
NH
Cl
Cl
NH+Cl-
Cl
Nornitrogen mustard
Aziridine
Sodium phosphate
and
Carbon dioxide
CH3
OPO3Na2
ON
O
Cl
Cl Estermustine Sodium Phosphate
Emcyt® - Pharmacia & Upjohn
• Used for metastatic carcinoma of the prostate
• Promoiety also a drug!
• Prodrug is selectively taken up into estrogen receptor positive cells then
urethane linkage is hydroylzed
• 17-alphaestradiol slow prostate cell growth
• Nornitrogen mustard is a weak alkylating agent

2. Functional Groups in Prodrugs
• Carboxylic acids and Alcohols: Most common type of prodrug
Drug O
Promoiety
O
OH Promoiety
Promoiety O
Drug
O
Drug OH
O
Promoiety OH
O
OH Drug
or
+
+
• Types of esterase enzymes mediating the hydrolysis process
• Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase,
Carboxypeptidase, Cholinesterase
• Bacterial microflora enzymes
• Wide number of choices of promoiety alcohols available
• Steric, electronic and hydrophobicity properties allow rate and extent of
hydrolysis to be controlled

3. O
CH3
O
O
O
O
OH
CH3
CH3
O
CH3
CH3
CH3
OH
CH3
CH3
OH
O
O
CH3
OH
CH3
OMe
CH3
O
NH(CH3
)2
+-SO4
Erthromycin estolate
Ilosone® - Eli Lilly
caps,tabs, suspension
Antibiotic used to treat
upper and lower respiratory
infections (URI or LRI),
Legionnaire's disease,
skin infections
• Erythromycin is a very bitter substance easily destroyed at acidic pH
• Propionate ester is to increase lipid solubility for improved absorption
• Ester must be hydrolyzed for antibacterial activity
• Lauryl sulfate salt – absorption not affected by food, less bitter after
taste and is acid stable
Functional Groups in Prodrugs

4. Esters Failure as Prodrugs
N
SN
H
O
O
CO2R2
H
R1
R3
R2 = ethyl, propyl, butyl, phenyl
Cephalosporin esters
Esterases
NO REACTION!
N
SN
H
O
O
CO2R2
H
CH3
CH3
R1
R2 = ethyl, propyl, butyl, phenyl
Penicillin esters

5. b-Lactam prodrug – Double
esters
N
S N
SN
H
O
O
H
NH2
OMe
OMe
O
O
CH3
O
OCH3
O
CH3
CH3
N
S N
SN
H
O
O
H
NH2
OMe
OMe
O
O
O
CH3
H
CH3
OH
CH3
CH3
CO2 +
N
S N
SN
H
O
O
H
NH2
OMe
OMe
O
O
O
CH3
CH3
+
Active Drug
HO-Esterase
Esterase
H2O
Vantin® – Pharmacia & Upjohn
URI, UTI, Gonorrhea, skin
infections
Taking with food
increases absorption
Why?
Increase
absorption
Avoid acid
catalyzed
decomposition