2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: Structure activity relationships of the 2-oxy pyridine C-region

Shivaji A. Thorat, Dong Wook Kang, Hyungchul Ryu, Myeong Seop Kim, Ho Shin Kim, Jihyae Ann, Taehwan Ha, Sung Eun Kim, Karam Son, Sun Choi, Peter M. Blumberg, Robert Frank, Gregor Bahrenberg, Klaus Schiene, Thomas Christoph, Jeewoo Lee

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22 Scopus citations


The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4- methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.

Original languageEnglish
Pages (from-to)589-602
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 2013

Bibliographical note

Funding Information:
This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) ( R11-2007-107-02001-0 ), Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ), the Ewha Global Top 5 Grant 2011 and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI (Project Z1A BC 005270 ).


  • Analgesic
  • Capsaicin
  • Molecular modeling
  • TRPV1 antagonists


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