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Bioorg Med Chem. 2008 Sep 15;16(18):8516-25. doi: 10.1016/j.bmc.2008.08.005. Epub 2008 Aug 7.

Tetrahydropyridine-4-carboxamides as novel, potent transient receptor potential vanilloid 1 (TRPV1) antagonists.

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  • 1Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Dept R4PM, AP10-207, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. brian.s.brown@abbott.com

Abstract

A series of 1,2,3,6-tetrahydropyridyl-4-carboxamides, exemplified by 6, have been synthesized and evaluated for in vitro TRPV1 antagonist activity, and in vivo analgesic activity in animal pain models. The tetrahydropyridine 6 is a novel TRPV1 receptor antagonist that potently inhibits receptor-mediated Ca2+ influx in vitro induced by several agonists, including capsaicin, N-arachidonoyldopamine (NADA), and low pH. This compound penetrates the CNS and shows potent anti-nociceptive effects in a broad range of animal pain models upon oral dosing due in part to its ability to antagonize both central and peripheral TRPV1 receptors. The SAR leading to the discovery of 6 is presented in this report.

PMID:
18722778
[PubMed - indexed for MEDLINE]
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