期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 2, 页码 727-742出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.11.049
关键词
TRPM8; TRPM8 antagonist; Phenylglycinamide; KPR-2579; Ugi reaction; OAB
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-aminopropy1)-2-([(3-methylphenyemethyl]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. (C) 2016 Elsevier Ltd. All rights reserved.
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