title: Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites.
abstract: 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.
authors.affiliation: Neurogen Corporation, Branford, CT 06405, USA. kjhodgetts@aol.com
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hodgetts
authors.forename: Charles A
authors.initials: CA
authors.lastname: Blum
authors.forename: Timothy
authors.initials: T
authors.lastname: Caldwell
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Bakthavatchalam
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Scott
authors.initials: S
authors.lastname: Capitosti
authors.forename: James E
authors.initials: JE
authors.lastname: Krause
authors.forename: Daniel
authors.initials: D
authors.lastname: Cortright
authors.forename: Marci
authors.initials: M
authors.lastname: Crandall
authors.forename: Beth Ann
authors.initials: BA
authors.lastname: Murphy
authors.forename: Susan
authors.initials: S
authors.lastname: Boyce
authors.forename: A
authors.initials: A
authors.lastname: Brian Jones
authors.forename: Bertrand L
authors.initials: BL
authors.lastname: Chenard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry; D010146:Pain / Q000188:drug therapy; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009287:Naphthyridines; D011719:Pyrazines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat