2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: Structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3- ylmethyl) C-region

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 StockhausenBabette Y. Kögel, Klaus Schiene, Thomas Christoph, Jeewoo Lee

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Abstract

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; IC50(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.

Original languageEnglish
Pages (from-to)8392-8408
Number of pages17
JournalJournal of Medicinal Chemistry
Volume55
Issue number19
DOIs
StatePublished - 11 Oct 2012

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