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

机译：高效哌啶二酮类芳香化酶抑制剂的合成，评估和QSAR研究。

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摘要

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 scc 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 -logIC50 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 micromol/kg body wt compound 2 was superior to CHAG and thus might be a candidate for the treatment of breast cancer.
机译：描述了新的被环烷基和环烷基烷基取代的3-（4-氨基苯基）-哌啶-2,6-二酮的合成及其作为芳香酶抑制剂的评价。其中7种新化合物的体外活性比先前临床候选的环己基化合物（CHAG）更高：环庚基（1），环庚基甲基（2），环己基甲基（3），环戊基甲基（4），1-金刚烷基甲基（6）， 2-环己基乙基（7）和2-环戊基乙基（8）。化合物3的活性最高，超过氨基谷氨酰胺（AG）和CHAG的效力分别为356和3倍，并达到了fadrozole的活性。除4外，其他强效芳香化酶抑制剂对P450 scc的活性均低于AG。所选化合物对P450 18的抑制作用很小。在包括类似的非环状烷基取代的哌啶二酮的QSAR研究中，发现logP和-logIC50之间存在线性关系。体内测试表明，化合物1、3、4、6和7与CHAG一样有效地抑制未成熟Sprague-Dawley大鼠的雄激素刺激的子宫生长。剂量为8.6 micromol / kg体重时，化合物2优于CHAG，因此可能是治疗乳腺癌的候选药物。

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