Inhibition of Aromatase (P450Arom) by some 1-(Benzofuran-2-ylmethyl)imidazoles

Abstract

Studies of a series of 1-(benzofuran-2-ylmethyl)imidazoles, 1–5, previously proposed as potential agents for prostatic cancer by their inhibition of 17β-hydroxylase:17,20-lyase (P450 17), have been extended to their selectivity against placental microsomal aromatase (P450Arom) in man.The compounds were 3–7-fold more potent than aminoglutethimide and had some selectivity for P450 17 as expressed by the ratio (IC50 P450Arom)/(IC50 P450) 17)/17.0 (2), 10.3(3), 34.6(4) and 42.0(5), where IC50 is the concentration resulting in 50% inhibition. The lower potency of 1–5 towards P450Arom compared with the racemic α-phenyl-substituted compounds (6, 80–1000 x aminoglutethimide) and some racemic α-methyl (8.5 and 12.2 x aminoglutethimide) and α-ethyl (12.1 and 32.9 x aminoglutethimide) analogues has been rationalized.This work selectively extends studies of the P450 17 inhibitor 5, a potential prostatic cancer agent, towards other cytochrome P450 enzymes in the steroidogenic pathway and provides a general method for determining the relative influence of chemical manipulation of a parent inhibitor towards two enzymes in the pathway using additional literature data.