杂芳基取代二氢萘和茚的合成与评价：用于治疗充血性心力衰竭和心肌纤维化的醛固酮合酶（CYP11B2）强效和选择性抑制剂
Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis.
作者信息
Voets Marieke, Antes Iris, Scherer Christiane, Müller-Vieira Ursula, Biemel Klaus, Marchais-Oberwinkler Sandrine, Hartmann Rolf W
机构信息
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbruecken, Germany.
出版信息
J Med Chem. 2006 Apr 6;49(7):2222-31. doi: 10.1021/jm060055x.
In this study, the synthesis and biological evaluation of heteroaryl-substituted dihydronaphthalenes and indenes (1-16) is described. The compounds were tested for activity by use of human CYP11B2 expressed in fission yeast and V79 MZh cells and for selectivity by use of human CYP11B1, CYP17, and CYP19. The most active inhibitor was the 6-methoxydihydronaphthalene 4 (IC(50) = 2 nM), showing a K(i) value of 1.3 nM and a competitive type of inhibition. The 5-methoxyindene 3 was found to be the most selective CYP11B2 inhibitor (IC(50) = 4 nM; CYP11B1 IC(50) = 5684 nM), which also showed only marginal inhibition of human CYP3A4 and CYP2D6. Docking and molecular dynamics studies using our homology-modeled CYP11B2 structure were performed to understand some structure-activity relationships. Caco-2 cell experiments revealed highly cell-permeable compounds, and metabolic studies with 4 using rat liver microsomes showed sufficient stability.
本研究描述了杂芳基取代的二氢萘和茚（1-16）的合成及生物学评价。利用在裂殖酵母和V79 MZh细胞中表达的人CYP11B2对这些化合物进行活性测试，并利用人CYP11B1、CYP17和CYP19进行选择性测试。活性最高的抑制剂是6-甲氧基二氢萘4（IC(50)=2 nM），其K(i)值为1.3 nM，呈竞争性抑制类型。发现5-甲氧基茚3是最具选择性的CYP11B2抑制剂（IC(50)=4 nM；CYP11B1的IC(50)=5684 nM），对人CYP3A4和CYP2D6也仅表现出微弱抑制作用。利用我们同源建模的CYP11B2结构进行对接和分子动力学研究，以了解一些构效关系。Caco-2细胞实验显示这些化合物具有高度的细胞通透性，用大鼠肝微粒体对4进行的代谢研究表明其具有足够的稳定性。
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