2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure鈥揂ctivity Relationships of 2-Amino Derivatives in the N-(6-

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• 作者：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. K枚gel ; Klaus Schiene ; Thomas Christoph ; Jeewoo Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8392-8408
• 全文大小：607K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

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.