Analogues of Aminoglutethimide: Selective Inhibition of Aromatase

Article abstract of DOI:10.1021/jm00380a009

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 (K_i-1.1 μM; value for 1, 0.60 μM), which exhibits a type II difference spectrum (K_s = 0.28 μM; value for 1, 0.13 μM) 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