title: The discovery of potent glycine transporter type-2 inhibitors: design and synthesis of phenoxymethylbenzamide derivatives.
abstract: We describe the discovery of phenoxymethylbenzamide derivatives as a novel class of glycine transporter type-2 (GlyT-2) inhibitors. We found hit compound 1 (human GlyT-2, IC50=4040 nM) in our library and converted its 1-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)pyrrolidin-3-yl group to an 1-(N,N-dimethylaminopropyl)piperidyl group and its tert-butyl group to a trifluoromethyl group to obtain N-(1-(3-(dimethylamino)propyl)piperidin-4-yl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (20). Compound 20 showed good inhibitory activity against human GlyT-2 (IC50=15.3 nM) and exhibited anti-allodynia effects in a mouse neuropathic pain model.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: eiki_takahashi@nts.toray.co.jp.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: tadamasa_arai@nts.toray.co.jp.
authors.forename: Tadamasa
authors.initials: T
authors.lastname: Arai
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: masato_akahira@nts.toray.co.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Akahira
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: mayumi_nakajima@nts.toray.co.jp.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: kazumi_nishimura@nts.toray.co.jp.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishimura
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: yu_omori@nts.toray.co.jp.
authors.forename: Yu
authors.initials: Y
authors.lastname: Omori
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: hiroki_kumaga@nts.toray.co.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kumagai
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: tomohiko_suzuki@nts.toray.co.jp.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: ryoji_hayashi2@nts.toray.co.jp.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hayashi
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; C493271:SLC6A5 protein, human
keywords: Glycine transporter type-2 inhibitor; Neuropathic pain; Phenoxymethylbenzamide derivatives