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 …

…, RG Schmidt, EK Bayburt, S DiDomenico…

文献索引：ABBOTT LABORATORIES; GOMTSYAN, Arthur R.; VOIGHT, Eric A.; BAYBURT, Erol K.; CHEN, Jun; DAANEN, Jerome F.; DIDOMENICO, Stanley, Jr.; KORT, Michael E.; KYM, Philip R.; MCDONALD, Heath A.; PERNER, Richard J.; SCHMIDT, Robert G. Patent: WO2010/45402 A1, 2010 ; Location in patent: Page/Page column 61-62 ; WO 2010/045402 A1

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被引用次数: 14

摘要

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- ...