title: Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists.
abstract: Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cold and chemical substances, and antagonists of this channel have been considered to be effective for pain and urinary diseases. N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 antagonist, was proposed to be effective for overactive bladder and painful bladder syndrome; however, there is a potential risk of low blood pressure. We report herein the synthesis and structure-activity relationships of novel phenylglycine derivatives that led to the identification of KPR-2579 (20l), a TRPM8 selective antagonist. KPR-2579 reduced the number of icilin-induced wet-dog shakes and rhythmic bladder contraction in rats, with no negative cardiovascular effects at the effective dose.
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan. Electronic address: jun-ichi_kobayashi@pharm.kissei.co.jp.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Kobayashi
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hirasawa
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Fujimori
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakanishi
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Kamada
authors.affiliation: Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ikeda
mesh_terms: D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C470025:phenylglycinamide; D005998:Glycine
keywords: KPR-2579; OAB; Phenylglycinamide; TRPM8; TRPM8 antagonist; Ugi reaction