Structure-activity relationship studies and discovery of a potent transient receptor potential vanilloid (TRPV1) antagonist 4-[3-chloro-5-[(1 S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3, 6-dihydro-2 H-pyridine-1-carboxamide (V116517) as a clinical candidate for pain management

Laykea Tafesse, Toshiyuki Kanemasa, Noriyuki Kurose, Jianming Yu, Toshiyuki Asaki, Gang Wu, Yuka Iwamoto, Yoshitaka Yamaguchi, Chiyou Ni, John Engel, Naoki Tsuno, Aniket Patel, Xiaoming Zhou, Takuya Shintani, Kevin Brown, Tsuyoshi Hasegawa, Manjunath Shet, Yasuyoshi Iso, Akira Kato, Donald J. Kyle

Research output: Contribution to journalArticle

Abstract

A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.

Original languageEnglish (US)
Pages (from-to)6781-6794
Number of pages14
JournalJournal of medicinal chemistry
Volume57
Issue number15
DOIs
StatePublished - Aug 14 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Tafesse, L., Kanemasa, T., Kurose, N., Yu, J., Asaki, T., Wu, G., Iwamoto, Y., Yamaguchi, Y., Ni, C., Engel, J., Tsuno, N., Patel, A., Zhou, X., Shintani, T., Brown, K., Hasegawa, T., Shet, M., Iso, Y., Kato, A., & Kyle, D. J. (2014). Structure-activity relationship studies and discovery of a potent transient receptor potential vanilloid (TRPV1) antagonist 4-[3-chloro-5-[(1 S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3, 6-dihydro-2 H-pyridine-1-carboxamide (V116517) as a clinical candidate for pain management. Journal of medicinal chemistry, 57(15), 6781-6794. https://doi.org/10.1021/jm500818a