Analogues of aminoglutethimide: selective inhibition of cholesterol side-chain cleavage.
In our probing of 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 and the estrogen-forming system aromatase, targets in the action of 1 against hormone-dependent mammary tumors, analogues in several categories have been 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 analogue [4, 1-amino-3-ethyl-3-phenylpiperidine-2,6-dione] was three times as inhibitory (respective Ki values of 1, 2, and 4 are 14, 13, and 4.6 microM), 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 (11) with hydrazine and thermal cyclization of the resulting amide hydrazide (15) afforded an improved synthesis of 4. Analogues having a second amino substituent, either at C-5 (10) or at N-1 (14) of the piperidine-2,6-dione residue, were less inhibitory than was 1 toward desmolase and aromatase. Among analogues 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 the 3-amino-4-hydroxy analogue (21).
D000616:Aminoglutethimide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008190:Lyases / Q000037:antagonists & inhibitors; D011247:Pregnancy
D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; D002784:Cholesterol; D008190:Lyases