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

Bioorganic & medicinal chemistry (2016-12-15)
Jun-Ichi Kobayashi, Hideaki Hirasawa, Tetsuji Ozawa, Tomonaga Ozawa, Hiroo Takeda, Yoshikazu Fujimori, Osamu Nakanishi, Noboru Kamada, Tetsuya Ikeda
RESUMEN

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.

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Sigma-Aldrich
KPR-2579, ≥98% (HPLC)