Referenced in: none

Automatically associated channels: Kir2.3

Title: Stereospecific high-affinity TRPV1 antagonists: chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues.

Authors: HyungChul Ryu, Mi-Kyoung Jin, Su Yeon Kim, Hyun-Kyung Choi, Sang-Uk Kang, Dong Wook Kang, Jeewoo Lee, Larry V Pearce, Vladimir A Pavlyukovets, Matthew A Morgan, Richard Tran, Attila Toth, Daniel J Lundberg, Peter M Blumberg

Journal, date & volume: J. Med. Chem., 2008 Jan 10 , 51, 57-67

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18072720

Abstract
Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues were characterized as potent and stereospecific rTRPV1 antagonists. In particular, compounds 72 and 73 displayed high binding affinities, with K i values of 4.12 and 1.83 nM and potent antagonism with K i values of 0.58 and 5.2 nM, respectively, in rTRPV1/CHO cells. These values are comparable or more potent than those of 5-iodoRTX under the same assay conditions. A distinctive binding model that includes two hydrophobic pockets is proposed for this series of compounds based on docking studies of 57 and 72 with a homology model of the TM3/4 region of TRPV1.