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Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6)
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2018-03-22 , DOI: 10.1016/j.bmcl.2018.03.056
Keisuke Motoyama , Tsutomu Nagata , Jun Kobayashi , Akifumi Nakamura , Naoki Miyoshi , Miho Kazui , Ken Sakurai , Tomoko Sakakura

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.



中文翻译:

发现双环[4.3.0]壬烷衍生物DS88790512作为有效的,选择性的和口服生物利用型瞬态受体电位规范药物6(TRPC6)的阻滞剂

在这项研究中,我们旨在合成一种新型的瞬时受体电位规范6(TRPC6)阻断剂。已知抑制剂的氨基茚满骨架的sp 2碳原子被sp 3碳原子取代,从而增加了分子的复杂性,通过分数sp 3(Fsp 3)进行测量。代表性化合物双环[4.3.0]壬烷衍生物DS88790512抑制了TRPC6,IC 50值为11 nM。值得注意的是,DS88790512对hERG和hNa V 1.5通道表现出优异的选择性,并被确定为口服生物可利用的化合物。

更新日期:2018-03-22
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