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

Cited 15 time in Web of Science Cited 18 time in Scopus
Authors

Lee, Sunho; Kim, Changhoon; Ann, Jihyae; Thorat, Shivaji A.; Kim, Eunhye; Park, Jongmi; Choi, Sun; Blumberg, Peter M.; Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas; Lee, Jeewoo

Issue Date
2017-09
Publisher
Pergamon Press Ltd.
Citation
Bioorganic and Medicinal Chemistry Letters, Vol.27 No.18, pp.4383-4388
Abstract
A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)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 Ki(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. © 2017 Elsevier Ltd.
ISSN
0960-894X
Language
English
URI
https://hdl.handle.net/10371/150133
DOI
https://doi.org/10.1016/j.bmcl.2017.08.020
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