2. Academic Validation
  3. N-Aryl Indoles as a Novel Class of Potent NaV1.7 Inhibitors

N-Aryl Indoles as a Novel Class of Potent NaV1.7 Inhibitors

  • ACS Med Chem Lett. 2023 May 24;14(6):788-793. doi: 10.1021/acsmedchemlett.3c00079.
Narayan Karanjule 1,  Noriyuki Hayashi 1,  Sayaka Suzuki 1,  Toshifumi Tsuda 1,  Eri Tokumaru 1,  Kyosuke Tanaka 1,  Hiroko Kimoto 1,  Yuki Domon 1,  Sakiko Takahashi 1,  Kazufumi Kubota 1,  Yutaka Kitano 1,  Tomihisa Yokoyama 1,  Ryuta Koishi 2,  Chie Fujiwara 1,  Shinichi Inaba 1,  Daigo Asano 1,  Tomoko Sakakura 1,  Kiyoshi Takasuna 1,  Tsuyoshi Shinozuka 1
Affiliations

Affiliations

  • 1 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2 Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 37312847 DOI: 10.1021/acsmedchemlett.3c00079
Abstract

A novel class of potent NaV1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse NaV1.7 inhibitory activity, which resulted in the discovery of N-aryl indoles. The introduction of the 3-methyl group is crucial for high NaV1.7 in vitro potency. The adjustment of lipophilicity led to the discovery of 2e. Compound 2e (DS43260857) demonstrated high in vitro potencies against both human and mouse NaV1.7 with high selectivity over NaV1.1, NaV1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.

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