title: Inhibition and time-dependent inactivation of human placental aromatase by 3-oxo-17 beta-carboxamido steroids.
abstract: Several N,N-dialkyl-3-oxo-4-aza-17 beta-carboxamido steroids were found to be competitive inhibitors versus androstenedione (AND) and time-dependent inactivators of aromatase activity from human term placental microsomes. Inhibition constants (Kis) from dead-end inhibition analyses indicated interactions between these compounds and the enzyme over a 0.8-7 microM inhibitor concentration range. The affinity of these compounds for aromatase leading to the time-dependent loss of enzyme activity was several fold higher than that estimated by the steady-state kinetics, with rate constants of inactivation of 0.025-0.033 min-1. 3-Oxo-4-aza steroids lacking a 17 beta-carboxamide were found to be competitive inhibitors of AND for aromatase, but did not inactivate enzyme activity in a time-dependent manner. Steroids which did not contain a 4-aza substituent, but retained the 17 beta-carbamoyl functionality, were both inhibitors and inactivators of aromatase activity in the microsomes. The time-dependent loss of aromatase activity induced by these compounds was shown to require reducing equivalents as provided by NADPH. Hence, it is suggested that the inactivation of aromatase by compounds in this series is dependent on enzymatic activation in the presence of the N,N-dialkyl-17 beta-carbamoyl substituent.
authors: Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, PA 19406-0939.
authors: A T
authors: AT
authors: Greway
authors: M A
authors: MA
authors: Levy
mesh_terms: D000735:Androstenedione / Q000494:pharmacology; D047072:Aromatase Inhibitors; D001378:Azasteroids / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000201:enzymology; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D013256:Steroids / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; D001378:Azasteroids; D013256:Steroids; D013196:Dihydrotestosterone; D000735:Androstenedione; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one