Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3-ylmethyl) C-region.

Authors: Myeong Seop Kim, HyungChul Ryu, Dong Wook Kang, Seong-Hee Cho, Sejin Seo, Young Soo Park, Mi-Yeon Kim, Eun Joo Kwak, Yong Soo Kim, Rahul S Bhondwe, Ho Shin Kim, Seul-Gi Park, Karam Son, Sun Choi, Ian A DeAndrea-Lazarus, Larry V Pearce, Peter M Blumberg, Robert Frank, Gregor Bahrenberg, Hannelore Stockhausen, Babette Y Kögel, Klaus Schiene, Thomas Christoph, Jeewoo Lee

Journal, date & volume: J. Med. Chem., 2012 Oct 11 , 55, 8392-408

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22957803

Abstract
A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K(i(CAP)) = 0.2 nM; IC(50(pH)) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.