2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists

Hyungchul Ryu, Sejin Seo, Seong Hee Cho, Ho Shin Kim, Aeran Jung, Dong Wook Kang, Karam Son, Minghua Cui, Sun Hye Hong, Pankaz Kumar Sharma, Sun Choi, Peter M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore Stockhausen, Klaus Schiene, Thomas Christoph, Sven Frormann, Jeewoo Lee

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.

Original languageEnglish
Pages (from-to)4039-4043
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number16
DOIs
StatePublished - 15 Aug 2014

Bibliographical note

Funding Information:
This research was supported by Research Grants from Grunenthal, Germany, 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 ), Republic of Korea and in part by the Intramural Research Program of NIH , Center for Cancer Research, NCI, USA (Project Z1A BC 005270).

Keywords

  • Capsaicin
  • Molecular modeling
  • Resiniferatoxin
  • TRPV1 antagonist
  • Vanilloid receptor 1

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