杂原子插入 3,4-二氢-1H-喹啉-2-酮中，得到对人源和鼠源醛固酮合酶具有高效和选择性的抑制剂。
Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.
机构信息
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, D-66123 Saarbrücken, Germany.
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2 3, D-66123 Saarbrücken, Germany.
出版信息
Eur J Med Chem. 2015 Jan 27;90:788-96. doi: 10.1016/j.ejmech.2014.12.022. Epub 2014 Dec 13.
Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM).
醛固酮合酶（CYP11B2）通过皮质酮和 18-羟皮质酮将 11-脱氧皮质酮转化为醛固酮。CYP11B2 被认为是几种心血管疾病的新靶点，这些疾病与慢性升高的醛固酮水平有关，如高血压、充血性心力衰竭和心肌纤维化。在本文中，我们通过系统地引入杂原子和通过内酯部分的生物等排体交换将磺酰胺部分，优化了杂环取代的 3,4-二氢吡啶-2(1H)-酮作为 CYP11B 抑制剂。关于抑制人 CYP11B2 和对人酶 CYP11B1、CYP17 和 CYP19 的选择性的最有前途的化合物，已针对大鼠 CYP11B2 进行了抑制测试。因此，我们发现了化合物 4 和 9，它们对 hCYP11B2（IC50 < 1 nM）和相应的大鼠酶（4：64%，9：51%抑制，在 2 μM）具有很强的抑制作用。
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