title: From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist.
abstract: 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.
authors.affiliation: Neurogen Corporation, 35 N. E. Industrial Road, Branford, CT 06405, USA.
authors.forename: Xiaozhang
authors.initials: X
authors.lastname: Zheng
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hodgetts
authors.forename: Harry
authors.initials: H
authors.lastname: Brielmann
authors.forename: Alan
authors.initials: A
authors.lastname: Hutchison
authors.forename: Frank
authors.initials: F
authors.lastname: Burkamp
authors.forename: A
authors.initials: A
authors.lastname: Brian Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Blurton
authors.forename: Robert
authors.initials: R
authors.lastname: Clarkson
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Chandrasekhar
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Bakthavatchalam
authors.forename: Stéphane
authors.initials: S
authors.lastname: De Lombaert
authors.forename: Marci
authors.initials: M
authors.lastname: Crandall
authors.forename: Daniel
authors.initials: D
authors.lastname: Cortright
authors.forename: Charles A
authors.initials: CA
authors.lastname: Blum
mesh_terms: 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
chemical_list: D000577:Amides; D018712:Analgesics, Non-Narcotic; D011799:Quinazolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea