Analogues of aminoglutethimide: selective inhibition of aromatase.

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Foster AB, Jarman M, Leung CS, Rowlands MG, Taylor GN, Plevey RG, Sampson P

Analogues of aminoglutethimide: selective inhibition of aromatase.

J Med Chem. 1985 Feb;28(2):200-4.

PubMed ID

3968684 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Aminoglutethimide	Cytochrome P450 19A1	Ki (nM)	600	N/A	N/A	Details