title: Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit.
abstract: Inhibition of c-Kit has the potential to treat mast cell associated fibrotic diseases. We report the discovery of several aminoquinazoline pyridones that are potent inhibitors of c-Kit with greater than 200-fold selectivity against KDR, p38, Lck, and Src. In vivo efficacy of pyridone 16 by dose-dependent inhibition of histamine release was demonstrated in a rodent pharmacodynamic model of mast cell activation.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc, Thousand Oaks, CA 91320-1799, USA. ehu@amgen.com
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.forename: Andrew
authors.initials: A
authors.lastname: Tasker
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.forename: Jason
authors.initials: J
authors.lastname: Human
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Roland
authors.initials: R
authors.lastname: Bürli
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.forename: Perry
authors.initials: P
authors.lastname: Novak
authors.forename: Andrea
authors.initials: A
authors.lastname: Itano
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.forename: Violeta
authors.initials: V
authors.lastname: Yu
authors.forename: Yen
authors.initials: Y
authors.lastname: Nguyen
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Tudor
authors.forename: Matthew
authors.initials: M
authors.lastname: Plant
authors.forename: Shaun
authors.initials: S
authors.lastname: Flynn
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Meagher
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Gordon Y
authors.initials: GY
authors.lastname: Ng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D006636:Histamine Release / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011799:Quinazolines; D019009:Proto-Oncogene Proteins c-kit