A series of 2-sulfonamidopyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide were investigated as hTRPV1 ligands. Systematic modification on the 2-sulfonamido group provided highly potent TRPV1 antagonists. The N-benzyl phenylsulfonamide derivatives 12 and 23 in particular showed higher affinities than that of lead compound 1. Compound 12 exhibited strong analgesic activity in the formalin pain model. Docking analysis of its chiral S-form 12S in our hTRPV1 homology model indicated that its high affinity might arise from additional hydrophobic interactions not present in lead compound 1S.
Bibliographical noteFunding Information:
This research was supported by research grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2007-0056817 ) 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