Analogs of aminoglutethimide: selective inhibition of cholesterol side-chain cleavage

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Abstract
In probing the structural features responsible for the inhibitory activity of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] toward the cholesterol side-chain cleavage enzyme system desmolase [from bovine adrenal] and the estrogen-forming system aromatase [from human placenta], targets in the action of 1 against hormone-dependent mammary tumors, analogs in several categories were synthesized and evaluated. Of the known monoamino derivatives, the meta derivative [2, 3-(3-aminophenyl)-3-ethylpiperidine-2,6-dione] was as inhibitory toward desmolase as 1, and the N-amino analog [4, 1-amino-3-ethyl-3-phenylpiperidine-2,6-dione] was 3 times as inhibitory (Ki values of 1, 2, and 4 are 14, 13, and 4.6 .mu.M, respectively), but 2 was a weak inhibitor and 4 was a noninhibitor of aromatase. Another amino analogue [5, 5-amino-3-ethyl-3-phenylpiperidine-2,6-dione] inhibited neither enzyme system. Reaction of glutethimide with hydrazine and thermal cyclization of the resulting amide hydrazide afforded an improved synthesis of 4. Analogs having a 2nd amino substituent, either at C-5 or at N-1 of the piperidine-2,6-dione residue, were less inhibitory than was 1 toward desmolase and aromatase. Among analogs having little or no inhibitory activity were hydroxy derivatives of 1 and 2, namely, 3-(4-amino-3-hydroxyphenyl)-3-ethylpiperidine-2,6-dione (20) and 3-(3-amino-4-hydroxyphenyl)-3-ethylpiperidine-2,6-dione.