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

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• 作者：Jun-ichi Kobayashi ; ^{jun-ichi_kobayashi@pharm.kissei.co.jp} ; Hideaki Hirasawa ; Tetsuji Ozawa^a ; Tomonaga Ozawa ; Hiroo Takeda ; Yoshikazu Fujimori ; Osamu Nakanishi ; Noboru Kamada ; Tetsuya Ikeda^b
• 关键词：TRPM8 ; TRPM8 antagonist ; Phenylglycinamide ; KPR-2579 ; Ugi reaction ; OAB
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：727-742
• 全文大小：984 K
• 卷排序：25

文摘

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.