Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup

A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamid...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-08, Vol.21 (15), p.4436-4440
Hauptverfasser:	STELLWAGEN, John C, ADJABENG, George M, ROMINGER, Cynthia M, ROSSANESE, Olivia W, SMITHEMAN, Kimberly N, WATERSON, Alex G, UEHLING, David E, ARNONE, Marc R, DICKERSON, Scott H, CHAO HAN, HORNBERGER, Keith R, KING, Alastair J, MOOK, Robert A, PETROV, Kimberly G, RHEAULT, Tara R
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Amino Acid Substitution Animals Antineoplastic agents Binding Sites Biological and medical sciences Catalytic Domain Fluorine - chemistry General aspects Medical sciences Microsomes, Liver - metabolism Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Rats Structure-Activity Relationship Sulfonamides - chemistry
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Zusammenfassung:	A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.06.021