jyl-1421 and Neuralgia

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; IC(50(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.

Topics: Analgesics; Animals; Body Temperature; Capsaicin; CHO Cells; Cricetinae; Cricetulus; Dopamine; Hot Temperature; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Docking Simulation; Neuralgia; Pyridines; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Sulfonamides; TRPV Cation Channels