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

Narayan Karanjule; Noriyuki Hayashi; Sayaka Suzuki; Toshifumi Tsuda; Eri Tokumaru; Kyosuke Tanaka; Hiroko Kimoto; Yuki Domon; Sakiko Takahashi; Kazufumi Kubota; Yutaka Kitano; Tomihisa Yokoyama; Ryuta Koishi; Chie Fujiwara; Shinichi Inaba; Daigo Asano; Tomoko Sakakura; Kiyoshi Takasuna; Tsuyoshi Shinozuka

doi:10.1021/acsmedchemlett.3c00079

N-Aryl Indoles as a Novel Class of Potent Na_V1.7 Inhibitors

ACS Med Chem Lett. 2023 May 24;14(6):788-793. doi: 10.1021/acsmedchemlett.3c00079. eCollection 2023 Jun 8.

Authors

Narayan Karanjule¹, Noriyuki Hayashi¹, Sayaka Suzuki¹, Toshifumi Tsuda¹, Eri Tokumaru¹, Kyosuke Tanaka¹, Hiroko Kimoto¹, Yuki Domon¹, Sakiko Takahashi¹, Kazufumi Kubota¹, Yutaka Kitano¹, Tomihisa Yokoyama¹, Ryuta Koishi², Chie Fujiwara¹, Shinichi Inaba¹, Daigo Asano¹, Tomoko Sakakura¹, Kiyoshi Takasuna¹, Tsuyoshi Shinozuka¹

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
PMCID: PMC10258897 (available on 2024-06-08)
DOI: 10.1021/acsmedchemlett.3c00079

Abstract

A novel class of potent Na_V1.7 inhibitors has been discovered. The replacement of diaryl ether in compound I was investigated to enhance mouse Na_V1.7 inhibitory activity, which resulted in the discovery of N-aryl indoles. The introduction of the 3-methyl group is crucial for high Na_V1.7 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 Na_V1.7 with high selectivity over Na_V1.1, Na_V1.5, and hERG. In vivo evaluations revealed 2e demonstrating potent efficacy in PSL mice with excellent pharmacokinetics.