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2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region

Title
2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region
Authors
Thorat S.A.Kang D.W.Ryu H.Kim M.S.Kim H.S.Ann J.Ha T.Kim S.-E.Son K.Choi S.Blumberg P.M.Frank R.Bahrenberg G.Schiene K.Christoph T.Lee J.
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2013
Journal Title
European Journal of Medicinal Chemistry
ISSN
0223-5234JCR Link
Citation
vol. 64, pp. 589 - 602
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-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 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-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. © 2013 Elsevier Masson SAS. All rights reserved.
DOI
10.1016/j.ejmech.2013.04.003
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약학대학 > 약학과 > Journal papers
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