2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

作     者：Ryu, HyungChul Seo, Sejin Cho, Seong-Hee Kim, Ho Shin Jung, Aeran Kang, Dong Wook Son, Karam Cui, Minghua Hong, Sun-Hye Sharma, Pankaz Kumar Choi, Sun Blumberg, Peter M. Frank-Foltyn, Robert Bahrenberg, Gregor Stockhausen, Hannelore Schiene, Klaus Christoph, Thomas Frormann, Sven Lee, Jeewoo 

作者机构：Seoul Natl Univ Coll Pharm Pharmaceut Sci Res Inst Med Chem Lab Seoul 151742 South Korea Ewha Womans Univ Natl Leading Res Lab Mol Modeling & Drug Design Coll Pharm Sch Pharmaceut Sci Seoul 120750 South Korea Ewha Womans Univ Global Top Res Program 5 Seoul 120750 South Korea NCI Lab Canc Biol & Genet Ctr Canc Res NIH Bethesda MD 20892 USA Grunenthal GmbH Grunenthal Innovat D-52078 Aachen Germany Catholic Univ Deagu Coll Hlth & Med Sci Dept Pharmaceut Sci & Technol Gyongsan 712702 Gyeongsangbuk D South Korea 

出 版 物：《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 (生物有机化学与医药化学通讯)

年 卷 期：2014年第24卷第16期

页      面：4039-4043页

核心收录：

学科分类：0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 0703[理学-化学] 

基　　金：Research Grants from Grunenthal, Germany National Research Foundation of Korea (NRF) [R11-2007-107-02001-0] National Leading Research Lab (NLRL) program, Republic of Korea [2011-0028885] Intramural Research Program of NIH, Center for Cancer Research, NCI, USA [Z1A BC 005270] 

主　　题：Vanilloid receptor 1 TRPV1 antagonist Capsaicin Resiniferatoxin Molecular modeling 

摘      要：A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode. (C) 2014 Elsevier Ltd. All rights reserved.