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
What are the advantages of using clindamycin phosphate rather than clindamycin?
Much reduced pain at the injection site
In vivo half life 10 mins
What is the prodrug of fludarabine?
Fludarabine monophosphate
How can prodrugs be used to gain access across the blood brain barrier?
Redox dihydropyridine system coupled to estradiol
- can pass across the BBB but not back again after it has been oxidised to the nitronium ion
How is AZT activated?
Three consecutive phosphorylations
- AZT triphosphate
What do all nucleoside drugs need to be activated?
Three consecutive phosphorylations
What is the prodrug of acyclovir?
Valtex
Why is a prodrug for acyclovir needed?
Valtex bioavailability = 54%
Acyclovir bioavailability = 12 - 20%
define log p
LogP is a measure of lipophylicity of a molecule
what is a pro moiety ?
Promoiety A functional group used to modify the structure of pharmacologically active agents to improve physicochemical, biopharmaceutical or pharmacokinetic properties.
