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
Keisuke MotoyamaTomoko Sakakura

Abstract

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.

Citations

Sep 3, 2020·Cells·Xingjuan ChenAlexander G Obukhov
Apr 28, 2019·Proceedings of the National Academy of Sciences of the United States of America·Brian Leei LinSteven S Pullen
Feb 1, 2020·Pharmacology & Therapeutics·Hongbo WangMichael X Zhu
Jun 20, 2020·Drug Discovery Today·Sumit Kumar Poonam
Apr 4, 2019·Journal of Medicinal Chemistry·Swagat Sharma, Corey R Hopkins
Sep 10, 2021·Annual Review of Pharmacology and Toxicology·Robin S BonPiruthivi Sukumar

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