Pharmaceutical Chemistry: Physicochemical Properties, SAR and Prodrugs
Pharmaceutical Chemistry in GPAT covers medicinal chemistry, drug design, physicochemical properties, functional-group chemistry, stereochemistry and synthesis. Expect structure–activity reasoning rather than rote names.
Physicochemical rules
- Lipinski's rule of five: MW ≤500, logP ≤5, hydrogen-bond donors ≤5, acceptors ≤10. It predicts oral permeability, not potency.
- logP is for the neutral species; logD is pH-dependent. Ionisation follows Henderson–Hasselbalch.
- Bioisosteres replace a group with similar size/electronics (e.g., –COOH with tetrazole) to retain activity while changing metabolism or acidity.
- Prodrugs mask a polar group to improve absorption; they require enzymatic or chemical activation.
Worked example
Aspirin has pKa ≈3.5. At plasma pH 7.4, for a weak acid: pH = pKa + log([A−]/[HA]), so [A−]/[HA] = 10^(7.4−3.5) = 10^3.9 ≈ 7,940. Fraction ionised = 7,940/(7,940+1) ≈ 0.9999, i.e. about 99.99%. This explains why the drug is largely ionised in plasma but more lipophilic in the acidic stomach.
Traps
Using logD in place of logP for neutral molecules; forgetting that a chiral switch can alter both efficacy and clearance; assuming all prodrugs are esterase-activated; confusing Hofmann elimination with exhaustive methylation.