Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites.
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.
Hodgetts
Kevin J
KJ
Neurogen Corporation, Branford, CT 06405, USA. kjhodgetts@aol.com
Blum
Charles A
CA
Caldwell
Timothy
T
Bakthavatchalam
Rajagopal
R
Zheng
Xiaozhang
X
Capitosti
Scott
S
Krause
James E
JE
Cortright
Daniel
D
Crandall
Marci
M
Murphy
Beth Ann
BA
Boyce
Susan
S
Brian Jones
A
A
Chenard
Bertrand L
BL
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
D009287:Naphthyridines; D011719:Pyrazines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat