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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Ryu, HyungChul¹  Seo, Sejin¹  Cho, Seong-Hee¹  Kim, Ho Shin¹  Jung, Aeran¹  Kang, Dong Wook^1,6  Son, Karam^2,3  Cui, Minghua^2,3  Hong, Sun-Hye^2,3  Sharma, Pankaz Kumar^2,3  Choi, Sun^2,3  Blumberg, Peter M.⁴  Frank-Foltyn, Robert⁵  Bahrenberg, Gregor⁵  Stockhausen, Hannelore⁵  Schiene, Klaus⁵  Christoph, Thomas⁵  Frormann, Sven⁵  Lee, Jeewoo¹ 

[1] Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Med Chem Lab, Seoul 151742, South Korea

[2] Ewha Womans Univ, Natl Leading Res Lab Mol Modeling & Drug Design, Coll Pharm, Sch Pharmaceut Sci, Seoul 120750, South Korea

[3] Ewha Womans Univ, Global Top Res Program 5, Seoul 120750, South Korea

[4] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[5] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany

[6] Catholic Univ Deagu, Coll Hlth & Med Sci, Dept Pharmaceut Sci & Technol, Gyongsan 712702, Gyeongsangbuk D, South Korea

关键词: Vanilloid receptor 1;    TRPV1 antagonist;    Capsaicin;    Resiniferatoxin;    Molecular modeling;   

DOI  :  10.1016/j.bmcl.2014.05.074

来源: Elsevier

【 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.

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