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

  • J Med Chem. 2014 Aug 14;57(15):6781-94. doi: 10.1021/jm500818a.
Laykea Tafesse  1 ,  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
Affiliations
  • 1. Discovery Research, Purdue Pharma LP , 6 Cedar Brook Drive, Cranbury, New Jersey 08512, United States.
PMID: 25057800 DOI: 10.1021/jm500818a
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.

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