2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists

Jin Mi Kang, Sun Ok Kwon, Jihyae Ann, Sunho Lee, Changhoon Kim, Nayeon Do, Jin Ju Jeong, Peter M. Blumberg, Heejin Ha, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi, Robert Frank-Foltyn, Bernhard Lesch, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee

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A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.

Original languageEnglish
Article number128266
JournalBioorganic and Medicinal Chemistry Letters
StatePublished - 15 Sep 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Ltd


  • Analgesic
  • TRPV1 Antagonist
  • Vanilloid Receptor 1


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