Motoyama Keisuke, Nagata Tsutomu, Kobayashi Jun, Nakamura Akifumi, Miyoshi Naoki, Kazui Miho, Sakurai Ken, Sakakura Tomoko
End-Organ Disease Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Asubio Pharma Co. Ltd., 6-4-3 Minatojima-minamimachi Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan.
Bioorg Med Chem Lett. 2018 Jul 1;28(12):2222-2227. doi: 10.1016/j.bmcl.2018.03.056. Epub 2018 Mar 22.
In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp carbon atoms to increase the molecular complexity, measured by fraction sp (Fsp). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNa1.5 channels, and was identified as an orally bioavailable compound.
在本研究中，我们旨在合成一种新型的瞬时受体电位香草酸亚型6（TRPC6）阻滞剂。将已知抑制剂氨基茚骨架中的sp碳原子替换为sp碳原子，以增加分子复杂性，通过分数sp（Fsp）来衡量。代表性化合物双环[4.3.0]壬烷衍生物DS88790512对TRPC6的抑制IC值为11 nM。值得注意的是，DS88790512对人乙醚-a-去极化相关基因（hERG）通道和人钠通道1.5（hNa1.5）表现出优异的选择性，并被鉴定为一种口服生物可利用的化合物。
