Synthesis of new potent and selective aromatase inhibitors based on long-chained diarylalkylimidazole and diarylalkyltriazole molecule skeletons

A series of long-chained diarylalkylimidazoles and diarylalkyltriazoles wer e synthesized and evaluated for the inhibitory potency for aromatase (estro gen synthetase) activity in human placental microsomes. The relative specif icity of inhibition was evaluated by measuring the inhibition of cholestero l side-chain cleavage enzyme (desmolase) in human placental mitochondria an d the inhibition of 7-ethoxycoumarin O-deethylase (a typical drug-metaboliz ing enzyme activity) in rat liver microsomes. The structural requirements i ncluding substituent effects for the strongest potency and for the highest specificity were delineated. alpha,omega-Diarylalkyltriazoles and imidazole s were the most interesting molecules, in which the geometric and optical i somerism displayed remarkable selectivity for aromatase inhibition. (C) 200 0 Elsevier Science B.V. All rights reserved.