Design of ProdrugsProdrugs are compounds, which are inactive but are converted in the body to the active drug. They have been useful in tackling problems such as:Acid sensitivityPoor membrane permeabilityDrug toxicityBad taste andShort duration of actionTwo things are needed to consider when designing prodrugs:To ensure that the prodrug is effectively converted to the active drug once it is absorbed into the blood supplyTo ensure that any groups cleaved from the molecule are non-toxic.

1. Prodrugs to improve membrane permeability: a. Esters as prodrugs. Prodrugs have proved very useful in

temporarily masking an ‘awkward’ functional group, which is important to receptor binding, but hinders the drug from crossing cell membranes. For example, a carboxylic acid functional group may have an important role to play in binding the drug to a receptor via ionic or hydrogen bonding. But it may prevent the drug from crossing a fatty cell membrane. The answer is to protect the acid function as an ester. The less polar ester can cross fatty cell membranes and, once it is in the bloodstream, it is hydrolyzed back to the free acid by esterase in the blood.

Specific example: Enalpril is the prodrug for the antihypertensive agent enalaprilate, and Bacampicillin, which is a prodrug of ampicillin.

N

O

RO

O CO2H

CH3

Enalpril (R = Et); Enalaprilate (R = H)

O

NH

N

S

O

Me

Me

CO2R

HNH2

R =HCMe

O CO

O CH2Me Bacampicillin

R = H; Ampicillin

b. Levodopa is a prodrug for the neurotransmitter dopamine and as such has been used in the treatment of Parkinson’s disease, a condition primarily due to a deficiency of the neurotransmitter dopamine. Dopamine itself cannot be used since it is too polar to cross the blood-brain barrier. Levodopa is even more polar and seems unlikely prodrug. However it is an amino acid and is therefore recognized by the carrier proteins for amino acids and is carried across the cell membrane. Once it crosses the barrier, a decarboxylase enzyme removes the acid group and generates dopamine.HO

HONH2

CO2H

Levodopa

HO

HONH2

Dopamine

2. Prodrugs to prolong drug activity. Prodrugs are designed to be slowly converted to the active drug to prolong or sustain a drug’s activity.

Example: Diazepam (Valium) is a prodrug of Nordazepam. Nordazepam itself has sedative action but loses activity quite quickly because of metabolism and excretion. Therefore Diazepam (Valium) is used to lead a more sustained action.

N

N

Me O

Cl

Diazepam (Valium)

N

N

H O

Cl

N-Demethylation

Nordazepam

3. Prodrugs masking drug toxicity and side effects. Salicylic acid is a good painkiller, but causes gastric bleeding because of the free phenolic group. This is overcome by masking the phenol as an ester (aspirin). The ester is later hydrolyzed by esterase to free the active drug.

Prodrugs can be used to give a slow release of drugs, which would be too toxic to give directly. Propionaldehyde is useful in the aversion therapy of alcohol, but is not used itself since it is an irritant. However, the prodrug pargylene can be converted to propionaldehyde by enzymes in the liver.

H2C N

Me

H2C C CHC

H

OC CH

Pargylene

4. Prodrugs to lower solubility in water:Some drugs have a revolting taste. One way to avoid

this problem is to reduce their solubility in water so that they do not dissolve on the tongue. For example, the bitter taste of the antibiotic chloramphenicol can be avoided by using the palmitate ester, which is quickly hydrolyzed once swallowed.

O2N

H

ORHN

O

Cl

Cl

OH

R = H ChloramphenicolR = CO(CH2)14CH3 Chloramphenicol palmitateR = CO(CH2)2CO2H Chloramphenicol succinate

5. Prodrugs to improve solubility in water:Prodrugs have been used to increase the

solubility in water of drugs. This is particularly useful for drugs given intravenously so that higher concentrations and smaller volumes can be used. For example, the succinate ester of chloramphenicol increases the water solubility of chloramphenicol because of the extra carboxylic acid.