The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase

Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (10), p.3387-3391
Main Authors: Ren, Li, Ahrendt, Kateri A., Grina, Jonas, Laird, Ellen R., Buckmelter, Alex J., Hansen, Joshua D., Newhouse, Brad, Moreno, David, Wenglowsky, Steve, Dinkel, Victoria, Gloor, Susan L., Hastings, Gregg, Rana, Sumeet, Rasor, Kevin, Risom, Tyler, Sturgis, Hillary L., Voegtli, Walter C., Mathieu, Simon
Format: Article
Language:English
Subjects:
adenosine triphosphate
Administration, Oral
B-Raf
Biological and medical sciences
Biological Availability
chemistry
Crystallography, X-Ray
Drug Discovery
drugs
growth retardation
Kinase
Medical sciences
pharmacokinetics
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Pyridopyrimidin-7-one
Pyrimidinones - chemistry
Pyrimidinones - pharmacokinetics
Pyrimidinones - pharmacology
Structure based drug design
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Summary:Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.04.015