Stereospecific high-affinity TRPV1 antagonists: chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues |
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Authors: | Ryu HyungChul Jin Mi-Kyoung Kim Su Yeon Choi Hyun-Kyung Kang Sang-Uk Kang Dong Wook Lee Jeewoo Pearce Larry V Pavlyukovets Vladimir A Morgan Matthew A Tran Richard Toth Attila Lundberg Daniel J Blumberg Peter M |
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Affiliation: | Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Korea. |
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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. |
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