Optimising leads Flashcards
How would you increase the aqueous solubility or membrane permeability of a lead compound?
Ionisation usually results in improved dissolution and solubility in aq media. Passively permeable compounds have pKa between 4 and 11. Outside this range conc of neutral drug is too low. Therefore adjust pKa to improve permeability. Prodrugs are also used to improve membrane permeability
Why is the passive permeability of zwitterions really low?
logP is too low. At physiological pH they exist as a neutral molecule as there is no net charge due to balanced charges
Why does gabapentin work as a CNS active oral drug?
similar structure to amino acids which are polar and can be absorbed by GIT. It is taken up by active transport in protein transporters. Drugs similar in structure to peptides, AA and sugars work in same way.
How would you increase the chemical and metabolic stability of a lead?
Chemical stability: conversion to a more stable group & increasing steric hindrance around the carbonyl to block nucleophilic attack. Metabolic: decrease polarity, introduce groups at susceptible sites to block reaction, inclusion of F atom can block metabolism (CH to CF), reduce log D, use bioisostere. Block metabolic site and increase half life
How do bioisosteres reduce metabolism?
shifts position of susceptible group to make it unrecognizable to metabolic enzyme but must still be recognizable by target
How would you decrease the chemical and metabolic stability of a lead?
Metabolic: increase polarity, increase LogD
What are some other uses of prodrugs?
to prolong activity, to mask toxicity and side effects, to increase water solubility, to target drugs to specific tissues
Why are esters less stable than other related carbonyl functional groups?
because the strongly electron withdrawing nature of oxygen means the carbon remains strongly delta positive and resonance is not as high as it would be for an amine
