Characterization of 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729209) as a novel TRPV1 antagonist
| Autor: | Michael P. Maher, Sandra R. Chaplan, Jing Liu, Jason C. Rech, Brian Scott, William A. Eckert, Bryan James Branstetter, Hong Ao, Anne E. Fitzgerald, Yi Liu, Nyantsz Wu, Michele C. Rizzolio, Anindya Bhattacharya, Jamie M. Freedman, Alec D. Lebsack, Nadia Swanson, J. Guy Breitenbucher, Dong H. Li, Alan D. Wickenden, Kia Sepassi, Mena Kansagara |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Stereochemistry Guinea Pigs Analgesic TRPV1 TRPV Cation Channels Pharmacology Body Temperature Cell Line Mice chemistry.chemical_compound Dogs Pharmacokinetics medicine Animals Humans Volume of distribution Clinical Trials as Topic Antagonist Hypothermia Rats Bioavailability Thiazoles Pyrimidines Cough chemistry Hyperalgesia Capsaicin Female lipids (amino acids peptides and proteins) Hypotension medicine.symptom |
| Zdroj: | European Journal of Pharmacology. 663:40-50 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2011.05.001 |
| Popis: | As an integrator of multiple nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various painful disorders. Several TRPV1 antagonists have been advanced into clinical trials and the initial observations suggest that TRPV1 antagonism may be associated with mild hyperthermia and thermal insensitivity in man. However, no clinical efficacy studies have been described to date, making an assessment of risk:benefit impossible. Furthermore, it is not clear whether these early observations are representative of all TRPV1 antagonists and whether additional clinical studies with novel TRPV1 antagonists are required in order to understand optimal compound characteristics. In the present study we describe 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729309) as a novel, TRPV1 antagonist. JNJ-39729209 displaced tritiated resiniferotoxin binding to TRPV1 and prevented TRPV1 activation by capsaicin, protons and heat. In-vivo, JNJ-39729209 blocked capsaicin-induced hypotension, induced a mild hyperthermia and inhibited capsaicin-induced hypothermia in a dose dependent manner. JNJ-39729209 showed significant efficacy against carrageenan- and CFA-evoked thermal hyperalgesia and exhibited significant anti-tussive activity in a guinea-pig model of capsaicin-induced cough. In pharmacokinetic studies, JNJ-39729209 was found to have low clearance, a moderate volume of distribution, good oral bioavailability and was brain penetrant. On the basis of these findings, JNJ-39729209 represents a structurally novel TRPV1 antagonist with potential for clinical development. The advancement of JNJ-39729209 into human clinical trials could be useful in further understanding the analgesic potential of TRPV1 antagonists. |
| Databáze: | OpenAIRE |
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