Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue -, Pages 589-602Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.04.003
Keywords
TRPV1 antagonists; Analgesic; Molecular modeling; Capsaicin
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Funding
- Grunenthal
- National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]
- National Leading Research Lab (NLRL) program [2011-0028885]
- Ewha Global Top 5 Grant
- Intramural Research Program of NIH
- Center for Cancer Research, NCI [Z1A BC 005270]
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The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethylpyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 535 using our hTRPV1 homology model indicated that the A- and B-region 2-(3fluoro-4-methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively. (C) 2013 Elsevier Masson SAS. All rights reserved.
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