Concept

Prodrugs

A prodrug is an inactive derivative that will be converted to the active drug in vivo Prodrugs are used when drugs have unattractive physicochemical properties

Undesirable Properties
l

Steps in Prodrug Design

l l

Physical Properties
l l l

Poor aqueous solubility Low lipophilicity Chemical instability Poor distribution across biological membranes Good substrate for first-pass metabolism Rapid absorption/excretion when long-term effect desired Not site-specific

Identification of drug delivery problem Identification of desired physicochemical properties Selection of transport moiety which will
l l

Pharmacokinetic Properties
l l l

give prodrug desired transport properties be readily cleaved in the desired biological compartment

Reversible Derivatives Derivative Types

l

Small molecule
l l

Prodrug has MW in 200-500 g/mole range Called a low molecular weight prodrug conjugate drug reversibly to biomolecule
l l

Functional Group Derivative O O -COOH OR NHR Esters Amides Carboxylic Acid -OH Alcohol
O O R Esters

O R1 O O O R2 -Acyloxyalkyl esters

Macromolecule
l

O O OR Carbonate Esters

O R Ethers

antibody hormone Target specific cell type (cancer cells antigens) Extend duration of action (longer circulation life time) Improve solubility Improve chemical stability of therapeutic agent

Objectives
l l l l

O OH O P OH Phosphate Esters
O H N R Amides R R1 H N R2 Enamines

R1 O O O R2 -Acyloxyalkyl ethers
R1 N C Imines R2

-NH2 Amine

O H N OR Carbamates

O R1 O H N O O R2 N-Acyloxyalkyloxycarbonyl

Oral Bioavailability Exercise

l

Ampicillin Prodrugs
l l

Ampicillin is poorly absorbed from the GI tract (~30% absorbed) Show the form of ampicillin that will be observed in the intestine (pH ~8) Suggest prodrug forms of ampicillin that might be better absorbed after oral dosing
NH2 H N N O O C OH S
Ampicillin

Esters of ampicillin are not good esterase substrates due to the steric crowding -acyloxyalkyl esters or carbonates undergo initial enzymatic cleavage of the terminal ester to generate unstable intermediates Show the intermediate and determine why it is unstable and spontaneously generates ampicillin in vivo
NH2 Pivampicillin H N N O O C O O S O O O O NH2 Bacampicillin H N N C O O S O O

Ampicillin Generation In Vivo

Ampicillin
Pivampicillin Intermediate NH2 H N S O O O N C O OH

Transdermal Delivery
l

NH2 O

Patch-based delivery of drugs is becoming more common

l l

H N N O

+ H

O H

C O

Contraceptives Nicotine addiction therapy

Bacampicillin Intermediate NH2 H N S O O O N C O OH

Ampicillin
NH2 H N N O O C O S + H CH3 O

Delivery through the skin requires biphasic solubility

l l

Lipid solubility Water solubility

Biphasic Solubility
l

Transdermal Contraceptive Delivery

l l

Is logP ~ 0 sufficient to ensure biphasic solubility (and therefore dermal permeability)? Why or why not?

Levonorgestrel is a potent contraceptive What solubility properties need to be changed? Suggest prodrug derivatives that might be useful
Levonorgestrel OH C CH

Levonorgestrel Prodrugs
l

Reading
l l

l l

The two structures below enhance transdermal delivery 15 and 30 times over levonorgestrel Which shows the 30 x improvement? Why?
O O O C CH OH OH O O O C CH OH OH

Chapter 8 8.4 Problems 1-3, 5, 7