Discovery of aryl aminoquinazoline pyridones as potent, selective, and orally efficacious inhibitors of receptor tyrosine kinase c-Kit

  • J Med Chem. 2008 Jun 12;51(11):3065-8. doi: 10.1021/jm800188g.
Essa Hu  1 ,  Andrew Tasker ,  Ryan D White ,  Roxanne K Kunz ,  Jason Human ,  Ning Chen ,  Roland Bürli ,  Randall Hungate ,  Perry Novak ,  Andrea Itano ,  Xuxia Zhang ,  Violeta Yu ,  Yen Nguyen ,  Yanyan Tudor ,  Matthew Plant ,  Shaun Flynn ,  Yang Xu ,  Kristin L Meagher ,  Douglas A Whittington ,  Gordon Y Ng
Affiliations
  • 1. Department of Medicinal Chemistry, Amgen Inc, Thousand Oaks, CA 91320-1799, USA. [email protected]
PMID: 18447379 DOI: 10.1021/jm800188g
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.

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