title: Analogues of aminoglutethimide: selective inhibition of aromatase.
abstract: In exploring further the structural features that influence the relative efficacy of analogues of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] as inhibitors of the cholesterol side-chain cleavage enzyme system desmolase and the estrogen forming system aromatase, analogues have been synthesized in which the aminophenyl substituent is replaced by pyridyl or substituted pyridyl. The 4-pyridyl analogue 5 [3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a strong competitive inhibitor of aromatase (Ki = 1.1 microM; value for 1, 0.60 microM), which exhibits a type II difference spectrum (Ks = 0.28 microM; value for 1, 0.13 microM) but is noninhibitory toward desmolase. The 2- and 3-pyridyl analogues (3 and 4) inhibit neither enzyme system. 1-Amino-3-ethyl-3-phenylpiperidine-2,6-dione (2) is a strong and selective inhibitor of desmolase but the 4-pyridyl analogue 10 [1-amino-3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a weak inhibitor of desmolase and aromatase. Analogues of 5 having a less basic aromatic substituent, namely, the N-oxide 11 and the 2,3,5,6-tetrafluoro derivative 13, were also prepared. The latter is a weak inhibitor of aromatase and the former inhibits neither enzyme system.
mesh_terms: D000616:Aminoglutethimide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D006801:Humans; D007700:Kinetics; D008190:Lyases / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013739:Testosterone / Q000378:metabolism
chemical_list: D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; D013739:Testosterone; D010088:Oxidoreductases; D008190:Lyases