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Discovery of Aryl Aminoquinazoline Pyridones as Potent, Selective, and Orally Efficacious Inhibitors of Receptor Tyrosine Kinase c-Kit

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Department of Medicinal Chemistry, Department of Inflammation, Department of HTS and Molecular Pharmacology, Department of Pharmacokinetics and Drug Metabolism, Department of Molecular Structures, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799 Department of Medicinal Chemistry, Department of Small Molecule Process Development, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139
†Atomic coordinates and structure factors for cocrystal structures of compounds 1, 2, and 16 with V916T KDR can be accessed using PDB codes 3CP9, 3CPB, and 3CPC, respectively.
* To whom correspondence should be addressed. Phone: 805-313-5300 . Fax: 805-480-3016. E-mail: [email protected]. Address: Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799.
‡Department of Medicinal Chemistry, Amgen Inc.
§Department of Small Molecule Process Development, Amgen Inc.
∥Department of Inflammation, Amgen Inc.
⊥Department of HTS and Molecular Phamacology, Amgen Inc.
#Department of Pharmacokinetics and Drug Metabolism, Amgen Inc.
▽Department of Molecular Structures, Amgen Inc.
Cite this: J. Med. Chem. 2008, 51, 11, 3065–3068
Publication Date (Web):May 1, 2008
https://doi.org/10.1021/jm800188g
Copyright © 2008 American Chemical Society
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Abstract

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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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Experimental details and characterization of all compounds, biological methods as well as X-ray crystal data for 1, 2, and 16. This material is available free of charge via the Internet at http://pubs.acs.org.

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  29. N. David Karis, Wendy A. Loughlin, Ian D. Jenkins, Peter C. Healy. tert -Butyl 2-(3-acetylamino-2-oxo-1,2-dihydro-1-pyridyl)acetate. Acta Crystallographica Section E Structure Reports Online 2008, 64 (12) , o2492-o2493. https://doi.org/10.1107/S1600536808039810
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