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A series of pyridine derivatives in the C-region of N -((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as h TRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple h TRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo . [ABSTRACT FROM AUTHOR]

A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamideswere designed combining previously identified pharmacophoric elementsand evaluated as hTRPV1 antagonists. The SAR analysis indicated thatspecific hydrophobic interactions of the 2-amino substituents in theC-region of the ligand were critical for high hTRPV1 binding potency.In particular, compound 49Swas an excellent TRPV1 antagonist (Ki(CAP)= 0.2 nM; IC50(pH)= 6.3 nM) and was thus approximately100- and 20-fold more potent, respectively, than the parent compounds 2and 3for capsaicin antagonism. Furthermore,it demonstrated strong analgesic activity in the rat neuropathic modelsuperior to 2with almost no side effects. Compound 49Santagonized capsaicin inducedhypothermia in mice but showed TRPV1-related hyperthermia. The basisfor the high potency of 49Scompared to 2is suggested by docking analysis withour hTRPV1 homology model in which the 4-methylpiperidinyl group inthe C-region of 49Smadeadditional hydrophobic interactions with the hydrophobic region. [ABSTRACT FROM AUTHOR]