2. Academic Validation
  3. Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists

Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists

  • Bioorg Med Chem. 2017 Jan 15;25(2):727-742. doi: 10.1016/j.bmc.2016.11.049.
Jun-Ichi Kobayashi 1,  Hideaki Hirasawa 2,  Tetsuji Ozawa 2,  Tomonaga Ozawa 2,  Hiroo Takeda 2,  Yoshikazu Fujimori 2,  Osamu Nakanishi 2,  Noboru Kamada 2,  Tetsuya Ikeda 2
Affiliations

Affiliations

  • 1 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.
  • 2 Discovery Research, R&D, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotakakashiwabara, Azumino, Nagano 399-8304, Japan.
PMID: 27964995 DOI: 10.1016/j.bmc.2016.11.049
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.

Keywords

KPR-2579; OAB; Phenylglycinamide; TRPM8; TRPM8 antagonist; Ugi reaction.

Figures