Quantitative relationships between structure and microsomal oxidation rate of 1,4-dihydropyridines.

The oxidation rate of a series of 4-phenyl substituted 1,4-dihydropyridine esters was investigated in dog liver microsomes and was evaluated in relation to physiochemical properties as well as to antihypertensive effect. The relative rate of microsomal oxidation was mainly dependent on the substituents of the aromatic ring and almost unaffected by small changes in the ester substituents. A 20-fold variation in the microsomal oxidation rate was observed within a group of dichloro-substituted analogues. Generally, the highest oxidation rate was found with 2',6'-disubstituted derivatives, while compounds with substituents in position 4' exhibited longer half-lives. The oxidation rate increased with increased steric bulk, increased lipophilicity and increased electron withdrawal of the substituents in position 2'. The energies of the highest occupied molecular orbital (HOMO) were calculated and correlated with the oxidation rate of some of the dihydropyridine analogues. The antihypertensive effect appeared to be restricted to compounds with oxidation rates within a narrow range, indicating the unlikelihood of increasing the duration of the pharmacologic effect by stabilisation of the dihydropyridine system.