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Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Title
Pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
Authors
Lee, SunhoKim, ChanghoonAnn, JihyaeThorat, Shivaji A.Kim, EunhyePark, JongmiChoi, 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 LETTERS
ISSN
0960-894XJCR Link1464-3405JCR Link
Citation
vol. 27, no. 18, pp. 4383 - 4388
Keywords
Vanilloid receptor 1TRPV1 antagonistMolecular modeling
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methyl-sulfonamidophenyl) propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with K-i(CAP) = 0.1 nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360. (C) 2017 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmcl.2017.08.020
Appears in Collections:
약학대학 > 약학과 > Journal papers
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