Buzzetti F, Di Salle E, Longo A, Briatico G
Research and Development, Farmitalia Carlo Erba Srl, Milano, Italy.
Steroids. 1993 Nov;58(11):527-32. doi: 10.1016/0039-128x(93)90029-m.
Exemestane (6-methylenandrosta-1,4-diene-3,17-dione; FCE 24304) is an orally active irreversible aromatase inhibitor which is in phase II clinical evaluation for the potential therapy of postmenopausal breast cancer. A series of exemestane analogs, with modifications at the 6-methylene group and with additional reduction at the 17-keto group, were synthesized as potential metabolites and tested in vitro for their effect on human placental aromatase. All these new analogs were found to be less potent in inhibiting aromatase than exemestane. The most effective compound was the 17 beta-hydroxy-derivative (compound 2), which is 2.6-fold less potent than exemestane [50% inhibitory concentration (IC50) 69 and 27 nM, respectively]. The various C-6 modified derivatives of the 17-oxo series were found to inhibit the aromatase enzyme in the following descending order: 6-methylene (exemestane) > 6-spirooxirane (6) > 6 beta-hydroxymethyl (11) > 6-hydroxymethyl (7) > 6 beta-carboxy (13), showing IC50 values of 27, 206, 295, 2,300, and 7,200 nM, respectively. The 17 beta-hydroxy analogs of some of the above mentioned compounds were also synthesized (3,4,12) and found to be 3-8-fold less potent than the corresponding 17-keto analogs.
依西美坦（6-亚甲基雄甾-1,4-二烯-3,17-二酮；FCE 24304）是一种口服活性不可逆芳香化酶抑制剂，正处于治疗绝经后乳腺癌的II期临床评估阶段。合成了一系列依西美坦类似物，它们在6-亚甲基处有修饰，且在17-酮基处有额外还原，作为潜在代谢物，并在体外测试它们对人胎盘芳香化酶的作用。发现所有这些新类似物抑制芳香化酶的效力均低于依西美坦。最有效的化合物是17β-羟基衍生物（化合物2），其效力比依西美坦低2.6倍[半数抑制浓度（IC50）分别为69和27 nM]。发现17-氧代系列的各种C-6修饰衍生物抑制芳香化酶的顺序如下：6-亚甲基（依西美坦）>6-螺环氧乙烷（6）>6β-羟甲基（11）>6-羟甲基（7）>6β-羧基（13），IC50值分别为27、206、295、2300和7200 nM。还合成了上述一些化合物的17β-羟基类似物（3、4、12），发现其效力比相应的17-酮类似物低3-8倍。
