American Chemical Society
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Discovery of Novel 6,6-Heterocycles as Transient Receptor Potential Vanilloid (TRPV1) Antagonists

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journal contribution
posted on 2010-04-22, 00:00 authored by Charles A. Blum, Timothy Caldwell, Xiaozhang Zheng, Rajagopal Bakthavatchalam, Scott Capitosti, Harry Brielmann, Stéphane De Lombaert, Mark T. Kershaw, David Matson, James E. Krause, Daniel Cortright, Marci Crandall, William J. Martin, Beth Ann Murphy, Susan Boyce, A. Brian Jones, Glenn Mason, Wayne Rycroft, Helen Perrett, Rachael Conley, Nicola Burnaby-Davies, Bertrand L. Chenard, Kevin J. Hodgetts
The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund’s adjuvant (CFA) induced chronic inflammatory pain after oral administration.