2. Academic Validation
  3. 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)

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.
Keisuke Motoyama 1,  Tsutomu Nagata 2,  Jun Kobayashi 3,  Akifumi Nakamura 4,  Naoki Miyoshi 3,  Miho Kazui 5,  Ken Sakurai 6,  Tomoko Sakakura 6
Affiliations

Affiliations

  • 1 End-Organ Disease Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: motoyama.keisuke.g6@daiichisankyo.co.jp.
  • 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 hNaV1.5 channels, and was identified as an orally bioavailable compound.

Keywords

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

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