Unit 3 - Pro drugs 2 Flashcards
How can a drug be improved?
Synthesis of close structural analogues
- solubility
- lipophilicity
- stability to metabolism
What are the disadvantages with analogue synthesis?
Very easy to lose potency by making the slightly changes to a structure of an active drug
Making analogues is often resources demanding
- many analogues are needed
What are the most common types of prodrugs?
Ester prodrugs
What are prodrugs derived from?
Carboxylic acids
- the majority of pro-drugs fall into this category
- several different structural types
- esters
- amides
Which part of a carboxylic acid derivative prodrug is the drug part?
Either the acid or the other component can be the drug part
- alcohol
- amine
What type of enzyme systems are capable of ester or amide hydrolysis?
Esterases
Amidises
Why is a prodrug needed for Tamiflu?
It has a CLogP of 1.2
It has a bioavailability of 5%
Why are simple aliphatic and aromatic ester prodrugs often used?
Easy to prepare
Relatively chemically stable
Pro-moiety (A functional group used to modify the structure of pharmacologically active agents to improve physicochemical, biopharmaceutical or pharmacokinetic properties.) often non-toxic
Why is enalapril used as a pro-drug?
50 - 75% absorption
- enalaprilat has a < 12% absorption
What is the pro drug of salicylic acid ?
Aspirin
Why are amides as prodrugs less popular than esters?
Very slow rate of in vivo hydrolysis of amides
- regeneration of drug from prodrug
What are the exceptions to using amides as popular prodrugs?
Use of amino acids/peptides or other substituted amides
Give an example of an amide prodrug
LDZ - pro drug to diazepam
Describe the process of LDZ changing to diazepam
2 Steps:
1st step: aminopeptidase
2nd step: Chemical cyclisation
Which inorganic acid derivatives can be used as prodrugs?
Sulphuric acid and phosphoric acid derivatives have been used as prodrugs
- increase water solubility rather than lipophilicity
