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

Title
Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists
Authors
Ann, JihyaeJung, AeranKim, Mi-YeonKim, Hyuk-MinRyu, HyungChulKim, SunjooKang, Dong WookHong, SunhyeCui, MinghuaChoi, SunBlumberg, Peter M.Frank-Foltyn, RobertBahrenberg, GregorStockhausen, HanneloreChristoph, ThomasLee, Jeewoo
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2015
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN
0968-0896JCR Link1464-3391JCR Link
Citation
vol. 23, no. 21, pp. 6844 - 6854
Keywords
Vanilloid receptor 1TRPV1 antagonistsAnalgesic
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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 445 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 445 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. (C) 2015 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2015.10.001
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약학대학 > 약학과 > Journal papers
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