Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: Synthesis and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists.

Authors: Richard J Perner, John R Koenig, Stanley Didomenico, Arthur Gomtsyan, Robert G Schmidt, Chih-Hung Lee, Margaret C Hsu, Heath A McDonald, Donna M Gauvin, Shailen Joshi, Teresa M Turner, Regina M Reilly, Philip R Kym, Michael E Kort

Journal, date & volume: Bioorg. Med. Chem., 2010 Jul 1 , 18, 4821-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20570528

Abstract
The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted compounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical animal models of pain.