Discovery of (R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist w

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• 作者：Eric A. Voight ; Arthur R. Gomtsyan ; Jerome F. Daanen ; Richard J. Perner ; Robert G. Schmidt ; Erol K. Bayburt ; Stanley DiDomenico ; Heath A. McDonald ; Pamela S. Puttfarcken ; Jun Chen ; Torben R. Neelands ; Bruce R. Bianchi ; Ping Han ; Regina M. Reilly ; Pamela H. Franklin ; Jason A. Segreti ; Richard A. Nelson ; Zhi Su ; Andrew J. King ; James S. Polakowski ; Scott J. Baker ; Donna M. Gauvin ; LaGeisha R. Lewis ; Joseph P. Mikusa ; Shailen K. Joshi ; Connie R. Faltynek ; Philip R. Kym ; Michael E. Kort
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7412-7424
• 全文大小：448K
• ISSN：1520-4804

文摘

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.