α-Substituted 2-(3-fluoro-4-methylsulfonamidophenyl)acetamides as potent TRPV1 antagonists

Phuong Thao Tran, Ho Shin Kim, Jihyae Ann, Sung Eun Kim, Changhoon Kim, Mannkyu Hong, Van Hai Hoang, Van T.H. Ngo, Sunhye Hong, Minghua Cui, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee

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Abstract

A series of α-substituted acetamide derivatives of previously reported 2-(3-fluoro-4-methylsulfonamidophenyl)propanamide leads (1, 2) were investigated for antagonism of hTRPV1 activation by capsaicin. Compound 34, which possesses an α-m-tolyl substituent, showed highly potent and selective antagonism of capsaicin with Ki(CAP) = 0.1 nM. It thus reflected a 3-fold improvement in potency over parent 1. Docking analysis using our homology model indicated that the high potency of 34 might be attributed to a specific hydrophobic interaction of the m-tolyl group with the receptor.

Original languageEnglish
Article number22607
Pages (from-to)2326-2330
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number11
DOIs
StatePublished - 1 Jun 2015

Bibliographical note

Funding Information:
This research was supported by Research Grants from Grunenthal in Germany, Grants from the Korea Science and Engineering Foundation (KOSEF) ( NRF-2014M3A9B5073755 ) and National Leading Research Lab ( NLRL ) program ( 2011-0028885 ) in South Korea, and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270) in USA.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Keywords

  • Analgesic
  • Capsaicin
  • Molecular modeling
  • TRPV1 antagonist

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