title: Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors.
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.
authors.affiliation: New Drug Regulatory Affairs Department, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuroda
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kimoto
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Domon
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kitano
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimizugawa
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Sugita
authors.affiliation: Venture Science Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Koishi
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Asano
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shinozuka
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D008801:Mexiletine / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000187:drug effects*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D010880:Piperidines; D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine; C032727:piperidine
keywords: CNS side effects; High-throughput screening; Pain; Piperidine; Voltage-gated sodium channel