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t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Title
t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
Authors
Lee, SunhoKang, Dong WookRyu, HyungChulKim, ChanghoonAnn, JihyaeLee, HobinKim, EunhyeHong, SunhyeChoi, SunBlumberg, Peter M.Frank-Foltyn, RobertBahrenberg, GregorStockhausen, HanneloreChristoph, ThomasLee, Jeewoo
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2017
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN
0968-0896JCR Link1464-3391JCR Link
Citation
vol. 25, no. 8, pp. 2451 - 2462
Keywords
Vanilloid receptor 1TRPV1 antagonistsAnalgesic
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with K-i = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the AFB-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency. (C) 2017 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2017.03.004
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약학대학 > 약학과 > Journal papers
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