HyungChul Ryu, Sejin Seo, Myeong Seop Kim, Mi-Yeon Kim, Ho Shin Kim, Jihyae Ann, Phuong-Thao Tran, Van-Hai Hoang, Jieun Byun, Minghua Cui, Karam Son, Pankaz Kumar Sharma, Sun Choi, Peter M Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Babette-Yvonne Koegel, Thomas Christoph, Sven Frormann, Jeewoo Lee
A series of 2-aryl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed highly potent TRPV1 antagonism toward capsaicin comparable to previous lead 7. Among them, compound 9 demonstrated anti-allodynia in a mouse neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of 9 with our hTRPV1 homology model provided insight into its specific binding mode.
August 15, 2014: Bioorganic & Medicinal Chemistry Letters