Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor

  • J Med Chem. 2020 Sep 24;63(18):10204-10220. doi: 10.1021/acs.jmedchem.0c00259.
Tsuyoshi Shinozuka  1 ,  Hiroyuki Kobayashi  1 ,  Sayaka Suzuki  1 ,  Kyosuke Tanaka  1 ,  Narayan Karanjule  1 ,  Noriyuki Hayashi  1 ,  Toshifumi Tsuda  1 ,  Eri Tokumaru  1 ,  Masahiro Inoue  1 ,  Kiyono Ueda  2 ,  Hiroko Kimoto  1 ,  Yuki Domon  1 ,  Sakiko Takahashi  1 ,  Kazufumi Kubota  1 ,  Tomihisa Yokoyama  1 ,  Akiko Shimizugawa  1 ,  Ryuta Koishi  2 ,  Chie Fujiwara  1 ,  Daigo Asano  1 ,  Tomoko Sakakura  1 ,  Kiyoshi Takasuna  1 ,  Yasuyuki Abe  1 ,  Toshiyuki Watanabe  1 ,  Yutaka Kitano  1
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2. R&D Division, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 32392056 DOI: 10.1021/acs.jmedchem.0c00259
Abstract

A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.

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