Structure-activity relationships of the inhibition of human placental aromatase by imidazole drugs including ketoconazole.

The aim of the present study was to investigate the effectiveness of several imidazole drugs to inhibit human placental aromatase compared with the known inhibitors of aromatase, 4-hydroxyandrostenedione (4-OHA) and aminoglutethimide (AG). Inhibition was similar with both androstenedione and testosterone as substrates. The order of decreasing inhibitory effect (determined from ID50 values) was: 4-OHA greater than tioconazole greater than econazole greater than bifonazole greater than clotrimazole greater than micomazole greater than isoconazole greater than ketoconazole greater than AG greater than nimorazole. The imidazole drugs and AG were reversible inhibitors of aromatase activity, in contrast 4-OHA was an irreversible inhibitor. Astemizole inhibited less than 40% whereas metronidazole, carbimazole, mebendazole, tinidazole and thiabendazole inhibited less than 20% of aromatase activity at 100 mumol/l. The imidazole drugs and AG were without effect on 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid oxidoreductase activity. In contrast 4-OHA was found to be a potent, reversible inhibitor of 3 beta-HSD-I with an ID50 value of 2.15 mumol/l. A common structural feature of the imidazole drugs having an inhibitory effect was the presence of one or more aromatic rings on the N-1 substituent. In contrast, the imidazole drugs having the imidazole ring fused to a benzene ring, i.e. benzimidazoles (astemizole, mebendazole, thiabendazole) and those having an aliphatic side chain on the N-1 of the imidazole ring (carbimazole, metronidazole, nimorazole, tinidazole) were only weak inhibitors of aromatase.