Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution.
A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
Blum
Charles A
CA
Neurogen Corporation, 35 N. E. Industrial Road, Branford, CT 06405, USA. cablum@comcast.net
Zheng
Xiaozhang
X
Brielmann
Harry
H
Hodgetts
Kevin J
KJ
Bakthavatchalam
Rajagopal
R
Chandrasekhar
Jayaraman
J
Krause
James E
JE
Cortright
Daniel
D
Matson
David
D
Crandall
Marci
M
Ngo
Chu K
CK
Fung
Lawrence
L
Day
Marta
M
Kershaw
Mark
M
De Lombaert
Stéphane
S
Chenard
Bertrand L
BL
D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry; D007249:Inflammation / Q000188:drug therapy; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D010146:Pain / Q000188:drug therapy; D004364:Pharmaceutical Preparations / Q000737:chemistry; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000634:Aminoquinolines; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D004364:Pharmaceutical Preparations; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C494484:TRPV1 receptor