Discovery of Novel 6,6-Heterocycles as Transient Receptor Potential Vanilloid (TRPV1) Antagonists
| Autor: | Harry Brielmann, David J. Matson, Bertrand L. Chenard, Mark T. Kershaw, W. Rycroft, Nicola Burnaby-Davies, Marci Crandall, Stéphane De Lombaert, Kevin J. Hodgetts, William J. Martin, Rajagopal Bakthavatchalam, Beth Ann Murphy, Timothy M. Caldwell, G Mason, A. Brian Jones, Xiaozhang Zheng, Helen Perrett, Susan Boyce, James E. Krause, Daniel N. Cortright, Charles A. Blum, Rachael Conley, Scott M. Capitosti |
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| Rok vydání: | 2010 |
| Předmět: |
Hot Temperature
Pyridines TRPV1 Biological Availability Pain TRPV Cation Channels In Vitro Techniques Pharmacology Structure-Activity Relationship Transient receptor potential channel chemistry.chemical_compound Oral administration In vivo Chlorocebus aethiops Drug Discovery Noxious stimulus Animals Humans Naphthyridines Inflammation Analgesics Antagonist Rats Pyrimidines chemistry Discovery and development of TRPV1 antagonists Hyperalgesia Capsaicin Pyrazines COS Cells Microsomes Liver Quinazolines Quinolines Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 53:3330-3348 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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