Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup

John C Stellwagen; George M Adjabeng; Marc R Arnone; Scott H Dickerson; Chao Han; Keith R Hornberger; Alastair J King; Robert A Mook Jr; Kimberly G Petrov; Tara R Rheault; Cynthia M Rominger; Olivia W Rossanese; Kimberly N Smitheman; Alex G Waterson; David E Uehling

doi:10.1016/j.bmcl.2011.06.021

Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup

Bioorg Med Chem Lett. 2011 Aug 1;21(15):4436-40. doi: 10.1016/j.bmcl.2011.06.021. Epub 2011 Jun 16.

Authors

John C Stellwagen¹, George M Adjabeng, Marc R Arnone, Scott H Dickerson, Chao Han, Keith R Hornberger, Alastair J King, Robert A Mook Jr, Kimberly G Petrov, Tara R Rheault, Cynthia M Rominger, Olivia W Rossanese, Kimberly N Smitheman, Alex G Waterson, David E Uehling

Affiliation

¹ GlaxoSmithKline Oncology CEDD, Research Triangle Park, NC 27709-3398, United States. john.stellwagen@amgen.com

PMID: 21733693
DOI: 10.1016/j.bmcl.2011.06.021

Abstract

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.

MeSH terms

Administration, Oral
Amino Acid Substitution
Animals
Binding Sites
Catalytic Domain
Fluorine / chemistry
Microsomes, Liver / metabolism
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*

Substances

Protein Kinase Inhibitors
Sulfonamides
Fluorine
Proto-Oncogene Proteins B-raf