A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 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 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with Ki(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 44S in our hTRPV1 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.
Bibliographical noteFunding Information:
This research was supported by research Grants from Grünenthal in Germany, grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2007-0057057 ) and the National Leading Research Lab (NLRL) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of the NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in the USA.
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- TRPV1 antagonists
- Vanilloid receptor 1