Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.

Abstract A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for h TRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44 S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K i(CAP)  = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44 S in our h TRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.