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).

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.

• Authors: Keisuke Motoyama, Tsutomu Nagata, Jun Kobayashi, Akifumi Nakamura, Naoki Miyoshi, Miho Kazui, Ken Sakurai, Tomoko Sakakura
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 12 Pg. 2222-2227 (07 01 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 29752182 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Indans
• TRPC6 Cation Channel
• TRPC6 protein, human
• bicyclo(4.3.0)nonane

Topics

• Administration, Oral
• Animals
• Biological Availability
• Calcium Channel Blockers (administration & dosage, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Discovery
• Humans
• Indans (administration & dosage, chemistry, pharmacology)
• Mice
• Microsomes, Liver (chemistry, metabolism)
• Molecular Structure
• Structure-Activity Relationship
• TRPC6 Cation Channel (antagonists & inhibitors, metabolism)