title: 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 17beta-hydroxylase:17,20-lyase (P450 17), have been extended to their selectivity against placental microsomal aromatase (P450(Arom)) 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 P450(Arom))/(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 P450(Arom) compared with the racemic alpha-phenyl-substituted compounds (6, 80-1000 x aminoglutethimide) and some racemic alpha-methyl (8.5 and 12.2 x aminoglutethimide) and alpha-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.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, UK.
authors.forename: C P
authors.initials: CP
authors.lastname: Owen
authors.forename: P J
authors.initials: PJ
authors.lastname: Nicholls
authors.forename: H J
authors.initials: HJ
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: Whomsley
mesh_terms: D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology
chemical_list: D047072:Aromatase Inhibitors; D001572:Benzofurans; D004791:Enzyme Inhibitors; D007093:Imidazoles; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D007654:Ketoconazole