Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: derivatives with variable 1-alkyl and 3-alkyl substituents.

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Leung CS, Rowlands MG, Jarman M, Foster AB, Griggs LJ, Wilman DE

Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: derivatives with variable 1-alkyl and 3-alkyl substituents.

J Med Chem. 1987 Sep;30(9):1550-4.

PubMed ID
3625703 [ View in PubMed
]
Abstract

3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione (1) is a strong competitive inhibitor of human placental aromatase (Ki = 1.1 microM; testosterone as substrate) that, unlike the structurally related aromatase inhibitor aminoglutethimide (2), is not also an inhibitor of the cholesterol side-chain cleavage enzyme desmolase. An improved synthesis of 1 is described, which was readily adapted to the preparation of homologues in a series of 3-alkyl-3-(4-pyridyl)-piperidine-2,6-diones (6-13). Alkylation of 1 afforded a second series, comprising 1-alkyl-3-ethyl-3-(4-pyridyl)-piperidine-2,6-diones (14-23). Inhibitory activity toward aromatase was maximal in both series for the octyl derivatives. Respective Ki values for the competitive inhibition exerted by the 3-octyl (12) and the 1-octyl (21) analogues with testosterone as substrate were 0.09 and 0.12 microM. The compounds 1, 2, 12, and 21 differed in their relative potencies as inhibitors of the aromatization of testosterone and androstenedione. Respective Ki values were as follows: for 1, 1.1 and 14 microM (ratio 12.7); for 2, 0.6 and 1.8 microM (3); for 12, 0.09 and 0.20 microM (2.2); and for 21, 0.12 and 0.48 microM (4).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AminoglutethimideCytochrome P450 19A1Ki (nM)600N/AN/ADetails
AminoglutethimideCytochrome P450 19A1Ki (nM)1800N/AN/ADetails
AminoglutethimideCytochrome P450 19A1IC 50 (nM)14000N/AN/ADetails
AminoglutethimideCytochrome P450 19A1IC 50 (nM)8000N/AN/ADetails