From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist.
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.
Zheng
Xiaozhang
X
Neurogen Corporation, 35 N. E. Industrial Road, Branford, CT 06405, USA.
Hodgetts
Kevin J
KJ
Brielmann
Harry
H
Hutchison
Alan
A
Burkamp
Frank
F
Brian Jones
A
A
Blurton
Peter
P
Clarkson
Robert
R
Chandrasekhar
Jayaraman
J
Bakthavatchalam
Rajagopal
R
De Lombaert
Stéphane
S
Crandall
Marci
M
Cortright
Daniel
D
Blum
Charles A
CA
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D006801:Humans; D008968:Molecular Conformation; D010146:Pain / Q000188:drug therapy; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000577:Amides; D018712:Analgesics, Non-Narcotic; D011799:Quinazolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea