Stereospecific High-affinity TRPV1 Antagonists: Chiral N-(2-Benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide Analogues

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• 作者：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.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 10, 2008
• 年：2008
• 卷：51
• 期：1
• 页码：57 - 67
• 全文大小：803K
• 年卷期：v.51,no.1(January 10, 2008)
• ISSN：1520-4804

文摘

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 α-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 and73 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.