PubMed 25100568

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: 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 with analgesic efficacy.

Authors: 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

Journal, date & volume: J. Med. Chem., 2014 Sep 11 , 57, 7412-24

PubMed link:

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.