Synthesis, evaluation and QSAR studies of highly potent aromatase inhibitors of the piperidinedione type

The syntheses of new cycloalkyl- and cycloalkylalkyl-substituted 3-(4-aminophenyl)-piperidine-2,6-diones and their evaluation as aromatase inhibitors is described. Seven of the new compounds were more active in vitro than the cyclohexyl compound (CHAG), a former clinical candidate: cycloheptyl (1), cycloheptylmethyl (2), cyclohexylmethyl (3), cyclopentylmethyl (4), 1-adamantylmethyl (6), 2-cyclohexylethyl (7) and 2-cyclopentylethyl (8). Compound 3 was the most active, exceeding the potency of aminoglutethimide (AG) and CHAG by factors of 356 and 3, respectively, and reaching the activity of fadrozole. With the exception of 4, the other highly potent aromatase inhibitors were less active towards P450 see compared with AG. Selected compounds showed only little inhibition of P450 18. In a QSAR study including analogous non-cyclic alkyl-substituted piperidinediones a linear relationship between logP and -logIC(50) was found. Tested in vivo, compounds 1, 3,4, 6 and 7 inhibited androgen-stimulated uterine growth in immature Sprague-Dawley rats as potently as CHAG. At a dose of 8.6 mu mol/kg body wt compound 2 was superior to CHAG and thus might be a candidate for the treatment of breast cancer.