935517-67-2Relevant articles and documents
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
Kim, Myeong Seop,Ryu, Hyungchul,Kang, Dong Wook,Cho, Seong-Hee,Seo, Sejin,Park, Young Soo,Kim, Mi-Yeon,Kwak, Eun Joo,Kim, Yong Soo,Bhondwe, Rahul S.,Kim, Ho Shin,Lee, Jeewoo,Park, Seul-Gi,Son, Karam,Choi, Sun,Deandrea-Lazarus, Ian A.,Pearce, Larry V.,Blumberg, Peter M.,Frank, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Koegel, Babette Y.,Schiene, Klaus,Christoph, Thomas
, p. 8392 - 8408,17 (2020/09/15)
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.
