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)

Keisuke Motoyama; Tsutomu Nagata; Jun Kobayashi; Akifumi Nakamura; Naoki Miyoshi; Miho Kazui; Ken Sakurai; Tomoko Sakakura

doi:10.1016/j.bmcl.2018.03.056

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)

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2222-2227. doi: 10.1016/j.bmcl.2018.03.056. Epub 2018 Mar 22.

Authors

Keisuke Motoyama¹, Tsutomu Nagata², Jun Kobayashi³, Akifumi Nakamura⁴, Naoki Miyoshi³, Miho Kazui⁵, Ken Sakurai⁶, Tomoko Sakakura⁶

Affiliations

¹ End-Organ Disease Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
² Asubio Pharma Co. Ltd., 6-4-3 Minatojima-minamimachi Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan.
³ End-Organ Disease Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁴ Modality Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁵ Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁶ Medicinal Safety Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-16-13 Kitakasai Edogawa-ku, Tokyo 134-8630, Japan.

PMID: 29752182
DOI: 10.1016/j.bmcl.2018.03.056

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 hNa_V1.5 channels, and was identified as an orally bioavailable compound.

Keywords: Bicyclic molecule; Fsp(3); Ion channel; Na(V)1.5; hERG.

MeSH terms

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

Substances

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