Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2-3, P.O. Box 151150, D-66123 Saarbrücken, Germany.
J Med Chem. 2012 Aug 23;55(16):7080-9. doi: 10.1021/jm3004637. Epub 2012 Aug 3.
Postmenopausal women are at high risk for cardiovascular diseases because of the estrogen deficiency. As for postmenopausal breast cancer patients, this risk is even higher due to inhibition of estrogens biosyntheses in peripheral tissue by the aromatase (CYP19) inhibitors applied. Because estrogen deficiency results in significantly elevated aldosterone levels, which are a major cause of cardiovascular diseases, dual inhibition of CYP19 and CYP11B2 (aldosterone synthase) is a promising treatment for breast cancer and the coinstantaneous cardiovascular diseases. By combination of important structural features of known CYP19 and CYP11B2 inhibitors, we succeeded in obtaining compounds 3 and 5 as selective dual inhibitors with IC(50) values around 50 and 20 nM toward CYP19 and CYP11B2, respectively. These compounds showed also good selectivity toward CYP11B1 (selectivity factors (IC(50 CYP11B1)/IC(50 CYP11B2)) around 50) and CYP17 (no inhibition).
绝经后妇女由于雌激素缺乏而患心血管疾病的风险很高。对于绝经后乳腺癌患者，由于应用的芳香酶（CYP19）抑制剂抑制外周组织中雌激素的生物合成，这种风险甚至更高。由于雌激素缺乏导致醛固酮水平显著升高，这是心血管疾病的主要原因，因此，CYP19 和 CYP11B2（醛固酮合酶）的双重抑制是治疗乳腺癌和同时发生的心血管疾病的一种有前途的方法。通过结合已知的 CYP19 和 CYP11B2 抑制剂的重要结构特征，我们成功地获得了化合物 3 和 5，它们分别对 CYP19 和 CYP11B2 的抑制作用具有约 50 和 20 nM 的 IC50 值，是选择性双重抑制剂。这些化合物对 CYP11B1（选择性因子（IC50 CYP11B1/IC50 CYP11B2）约为 50）和 CYP17（无抑制作用）也具有良好的选择性。
