Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites. 2010

Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
Neurogen Corporation, Branford, CT 06405, USA. kjhodgetts@aol.com

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective 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. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.

UI MeSH Term Description Entries
D008253 Macaca mulatta A species of the genus MACACA inhabiting India, China, and other parts of Asia. The species is used extensively in biomedical research and adapts very well to living with humans. Chinese Rhesus Macaques,Macaca mulatta lasiota,Monkey, Rhesus,Rhesus Monkey,Rhesus Macaque,Chinese Rhesus Macaque,Macaca mulatta lasiotas,Macaque, Rhesus,Rhesus Macaque, Chinese,Rhesus Macaques,Rhesus Macaques, Chinese,Rhesus Monkeys
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009287 Naphthyridines A group of two-ring heterocyclic compounds consisting of a NAPHTHALENES double ring in which two carbon atoms, one per each ring, are replaced with nitrogens.
D010146 Pain An unpleasant sensation induced by noxious stimuli which are detected by NERVE ENDINGS of NOCICEPTIVE NEURONS. Suffering, Physical,Ache,Pain, Burning,Pain, Crushing,Pain, Migratory,Pain, Radiating,Pain, Splitting,Aches,Burning Pain,Burning Pains,Crushing Pain,Crushing Pains,Migratory Pain,Migratory Pains,Pains, Burning,Pains, Crushing,Pains, Migratory,Pains, Radiating,Pains, Splitting,Physical Suffering,Physical Sufferings,Radiating Pain,Radiating Pains,Splitting Pain,Splitting Pains,Sufferings, Physical
D011719 Pyrazines A heterocyclic aromatic organic compound with the chemical formula C4H4N2. Pyrazine
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006930 Hyperalgesia An increased sensation of pain or discomfort produced by minimally noxious stimuli due to damage to soft tissue containing NOCICEPTORS or injury to a peripheral nerve. Hyperalgesia, Tactile,Hyperalgesia, Thermal,Hyperalgia,Hyperalgia, Mechanical,Hyperalgia, Primary,Hyperalgia, Secondary,Allodynia,Allodynia, Mechanical,Allodynia, Tactile,Allodynia, Thermal,Hyperalgesia, Mechanical,Hyperalgesia, Primary,Hyperalgesia, Secondary,Hyperalgesic Sensations,Mechanical Allodynia,Mechanical Hyperalgesia,Tactile Allodynia,Thermal Allodynia,Allodynias,Hyperalgesias,Hyperalgesias, Thermal,Hyperalgesic Sensation,Mechanical Hyperalgia,Mechanical Hyperalgias,Primary Hyperalgia,Primary Hyperalgias,Secondary Hyperalgia,Secondary Hyperalgias,Sensation, Hyperalgesic,Sensations, Hyperalgesic,Thermal Hyperalgesia
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations

Related Publications

Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
September 1970, Journal of medicinal chemistry,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
November 1968, Journal of medicinal chemistry,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
February 2010, Pest management science,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
January 2017, European journal of medicinal chemistry,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
August 2008, Bioorganic & medicinal chemistry letters,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
November 2013, Bioorganic & medicinal chemistry letters,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
November 1987, Il Farmaco; edizione scientifica,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
July 2004, Bioorganic & medicinal chemistry letters,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
November 2012, Bioorganic & medicinal chemistry letters,
Kevin J Hodgetts, and Charles A Blum, and Timothy Caldwell, and Rajagopal Bakthavatchalam, and Xiaozhang Zheng, and Scott Capitosti, and James E Krause, and Daniel Cortright, and Marci Crandall, and Beth Ann Murphy, and Susan Boyce, and A Brian Jones, and Bertrand L Chenard
August 2009, Biochemical pharmacology,
Copied contents to your clipboard!