Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists.

Authors: Robert G Schmidt, Erol K Bayburt, Steven P Latshaw, John R Koenig, Jerome F Daanen, Heath A McDonald, Bruce R Bianchi, Chengmin Zhong, Shailen Joshi, Prisca Honore, Kennan C Marsh, Chih-Hung Lee, Connie R Faltynek, Arthur Gomtsyan

Journal, date & volume: Bioorg. Med. Chem. Lett., 2011 Mar 1 , 21, 1338-41

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21315587

Abstract
Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.