Steric factors in the inhibitory interaction of imidazoles with microsomal enzymes

Abstract

The ability of substituted imidazoles to bind to cytochrome P-450 (type II) and to inhibit microsomal drug-metabolizing enzyme activity is highly dependent on the position of the substituent in the imidazole ring. Compounds containing substituents in the 1-, 4(5)- and 1,5-positions are effective inhibitors of the epoxidation of aldrin in rat liver microsomes and armyworm ( Spodoptera eridania) gut preparations and exhibit low spectral dissociation constants ( K s . In contrast, compounds containing 2- and/or 4-substitutents are essentially inactive as inhibitors and exhibit high K s values (low binding). It appears that both binding and inhibition depend on the accessibility of the non-bonded electrons on the nitrogen atom at position — 3 of the ring.