The discovery of potent and selective 4-aminothienopyridines as B-Raf kinase inhibitors

A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50=5.1, 16.6nM) and cellular assay (IC50=0.2, 0.2μM), but also had an outstanding selec...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-01, Vol.23 (1), p.66-70
Hauptverfasser:	Tang, Jun, Lackey, Karen E., Dickerson, Scott H.
Format:	Artikel
Sprache:	eng
Schlagworte:	Aminopyridines - chemical synthesis Aminopyridines - chemistry Aminopyridines - metabolism B-Raf inhibitor bioassays chemistry Drug Design Drug Evaluation, Preclinical enzyme inhibitors Knowledge-based design Phenylurea Compounds - chemical synthesis Phenylurea Compounds - chemistry Phenylurea Compounds - metabolism phosphotransferases (kinases) Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - metabolism pyridines Structure-Activity Relationship Thienopyridines - chemical synthesis Thienopyridines - chemistry Thienopyridines - metabolism
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Zusammenfassung:	A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50=5.1, 16.6nM) and cellular assay (IC50=0.2, 0.2μM), but also had an outstanding selectivity profile against other kinases. A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC50=5.1, 16.6nM) and cellular assay (IC50=0.2, 0.2μM), but also had an outstanding selectivity profile against other kinases.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.11.020