Novel Pyridyl Substituted 4,5-Dihydro-[1,2,4]triazolo[4,3-a]quinolines as Potent and Selective Aldosterone Synthase Inhibitors with Improved in Vitro Metabolic Stability
Novel Pyridyl Substituted 4,5-Dihydro-[1,2,4]triazolo[4,3-a]quinolines as Potent and Selective Aldosterone Synthase Inhibitors with Improved in Vitro Metabolic Stability
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DOI：
10.1021/acs.jmedchem.5b00079
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发表时间：
2015-03-12
影响因子：
7.3
通讯作者：
Hartmann, Rolf W.
中科院分区：
文献类型：
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作者：
Hu, Qingzhong;Yin, Lina;Hartmann, Rolf W.
CYP 11B 2抑制是一种很有前途的治疗醛固酮过多引起的疾病的方法。为了改善先前报道的CYP 11B 2抑制剂在人肝错体中的代谢稳定性，通过基于配体和基于结构的药物设计方法的组合进行修饰，得到吡啶基4，5-二氢-[1，2，4]三唑并[4，3-a]喹诺酮。化合物26不仅表现出长得多的半衰期（t（1/2）>> 120分钟），而且表现出持续的抑制效力（IC 50 = 4.2 nM）和对CYP 11 B1（SF = 422）、CYP 17、CYP 19和一组肝酶的选择性。
CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t(1/2) >> 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes.