Knowledge-based design of 7-azaindoles as selective B-Raf inhibitors

We have identified the title compound 6h as a novel, potent, and selective B-Raf kinase inhibitor using knowledge-based design. The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-08, Vol.18 (16), p.4610-4614
Hauptverfasser:	Tang, Jun, Hamajima, Toshihiro, Nakano, Masato, Sato, Hideyuki, Dickerson, Scott H., Lackey, Karen E.
Format:	Artikel
Sprache:	eng
Schlagworte:	7-Azaindole Antineoplastic agents B-Raf kinase Biological and medical sciences Chemistry, Pharmaceutical - methods Drug Design General aspects Humans Indoles - pharmacology Inhibitory Concentration 50 Knowledge-based design Medical sciences Models, Biological Models, Chemical Molecular Structure Pharmacology. Drug treatments Phosphotransferases - metabolism Protein Kinase Inhibitors - antagonists & inhibitors Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - metabolism Structure-Activity Relationship Substrate Specificity
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Zusammenfassung:	We have identified the title compound 6h as a novel, potent, and selective B-Raf kinase inhibitor using knowledge-based design. The synthesis of a 7-azaindole series of novel, potent B-Raf kinase inhibitors using knowledge-based design was carried out. Compound 6h exhibits not only excellent potency in both the enzyme assay (IC 50 = 2.5 nM) and the cellular assay (IC 50 = 63 nM), but also has an outstanding selectivity profile against other kinases.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.07.019