Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors

Sayaka Suzuki; Takeshi Kuroda; Hiroko Kimoto; Yuki Domon; Kazufumi Kubota; Yutaka Kitano; Tomihisa Yokoyama; Akiko Shimizugawa; Ryusuke Sugita; Ryuta Koishi; Daigo Asano; Kazuhiko Tamaki; Tsuyoshi Shinozuka; Hiroyuki Kobayashi

doi:10.1016/j.bmcl.2015.09.005

Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5419-23. doi: 10.1016/j.bmcl.2015.09.005. Epub 2015 Sep 5.

Affiliations

¹ New Drug Regulatory Affairs Department, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
² Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
³ Biological Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁴ Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁵ Venture Science Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁶ Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 26358159
DOI: 10.1016/j.bmcl.2015.09.005

Abstract

A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.7 inhibitory activities with fair subtype selectivity over NaV1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin.

Keywords: CNS side effects; High-throughput screening; Pain; Piperidine; Voltage-gated sodium channel.

MeSH terms

Animals
Drug Discovery*
Humans
Inhibitory Concentration 50
Mexiletine / chemistry
Mexiletine / pharmacology
Mice
Molecular Structure
NAV1.7 Voltage-Gated Sodium Channel / drug effects*
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology*
Voltage-Gated Sodium Channel Blockers / chemical synthesis*
Voltage-Gated Sodium Channel Blockers / chemistry
Voltage-Gated Sodium Channel Blockers / pharmacology*

Substances

NAV1.7 Voltage-Gated Sodium Channel
Piperidines
Voltage-Gated Sodium Channel Blockers
Mexiletine
piperidine