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

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.

Citation

Tsuyoshi Shinozuka, Hiroyuki Kobayashi, Sayaka Suzuki, Kyosuke Tanaka, Narayan Karanjule, Noriyuki Hayashi, Toshifumi Tsuda, Eri Tokumaru, Masahiro Inoue, Kiyono Ueda, Hiroko Kimoto, Yuki Domon, Sakiko Takahashi, Kazufumi Kubota, Tomihisa Yokoyama, Akiko Shimizugawa, Ryuta Koishi, Chie Fujiwara, Daigo Asano, Tomoko Sakakura, Kiyoshi Takasuna, Yasuyuki Abe, Toshiyuki Watanabe, Yutaka Kitano. Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor. Journal of medicinal chemistry. 2020 Sep 24;63(18):10204-10220

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PMID: 32392056

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