Foye's Principles of Medicinal Chemistry

What the book covers

10 high-yield topics. Each has the points most often examined and links to practise them.

1. 1Drug design principles

   • Lipinski's rule of five predicts oral absorption from molecular weight, logP and hydrogen bond counts.
   • A pharmacophore is the minimum arrangement of features needed for activity.
   • Lead optimisation improves potency, selectivity and kinetics.
   • Higher lipophilicity improves membrane crossing but can raise toxicity and metabolism.
   Practise MCQsNotes: Drug Design Principles

2. 2Prodrugs

   • Enalapril is an ester prodrug hydrolysed to enalaprilat.
   • Levodopa crosses the blood-brain barrier and is converted to dopamine.
   • Clopidogrel and codeine need CYP activation.
   • Prodrugs improve absorption, taste, stability or targeting.
   Practise MCQsNotes: Prodrugs and Bioisosterism

3. 3Bioisosterism

   • Bioisosteres replace a group with one of similar size and electronics to keep activity.
   • A tetrazole replaces a carboxylic acid in ARBs such as losartan.
   • Fluorine often replaces hydrogen to block metabolism.
   • Bioisosteres can reduce toxicity or improve kinetics.
   Practise MCQsNotes: Prodrugs and Bioisosterism

4. 4Phase I metabolism

   • Oxidation by CYP450 is the most common phase I reaction.
   • Esters are hydrolysed faster than amides, so procaine is shorter acting than lidocaine.
   • N-dealkylation can give active metabolites, such as diazepam to desmethyldiazepam.
   • Paracetamol forms the toxic NAPQI by oxidation when glutathione runs out.
   Practise MCQsNotes: Drug Metabolism Chemistry

5. 5Phase II metabolism

   • Glucuronidation is the main conjugation reaction; neonates have low capacity (grey baby syndrome with chloramphenicol).
   • Acetylation is polymorphic (isoniazid, hydralazine, procainamide).
   • Methylation by TPMT inactivates thiopurines.
   • Morphine-6-glucuronide is an active conjugate that builds up in kidney failure.
   Practise MCQsNotes: Drug Metabolism Chemistry

6. 6Stereochemistry

   • Enantiomers can differ in activity; S-warfarin is more potent than R-warfarin.
   • Esomeprazole and levocetirizine are single-enantiomer versions of racemic drugs.
   • Thalidomide enantiomers interconvert in the body.
   • Receptors are chiral, so they can tell enantiomers apart.
   Practise MCQsNotes: Structure Activity Relationship

7. 7SAR of beta-lactams

   • The intact beta-lactam ring is essential for activity.
   • Bulky side chains (methicillin, flucloxacillin) protect against penicillinase.
   • An amino group (ampicillin, amoxicillin) widens the spectrum to some Gram-negatives.
   • Clavulanic acid and tazobactam inhibit beta-lactamases.
   Practise MCQsNotes: Structure Activity Relationship

8. 8SAR of CNS drugs

   • Benzodiazepines need an electron-withdrawing group at position 7 for activity.
   • Phenothiazines with a chlorine at position 2 (chlorpromazine) increase antipsychotic potency.
   • Barbiturates need two substituents at carbon 5 for sedative activity.
   • Increasing lipophilicity speeds onset in the CNS (thiopental).
   Practise MCQsNotes: Structure Activity Relationship

9. 9SAR of cardiovascular drugs

   • Beta blockers share an aryloxypropanolamine side chain; the S-isomer is active.
   • Dihydropyridines need the 1,4-dihydropyridine ring; oxidation to pyridine destroys activity.
   • ACE inhibitors carry a zinc-binding group (sulfhydryl, carboxylate or phosphinate).
   • Captopril's sulfhydryl group is linked to rash and taste disturbance.
   Practise MCQsNotes: Structure Activity Relationship

10. 10Drug name stems

    • -olol: beta blocker; -pril: ACE inhibitor; -sartan: ARB.
    • -statin: HMG-CoA reductase inhibitor; -prazole: proton pump inhibitor.
    • -mab: monoclonal antibody; -tinib: tyrosine kinase inhibitor.
    • -gliptin: DPP-4 inhibitor; -gliflozin: SGLT2 inhibitor.
    Practise MCQsCheat sheet