Non-oxime pyrazole based inhibitors of B-Raf kinase

Bradley J Newhouse; Joshua D Hansen; Jonas Grina; Mike Welch; George Topalov; Nicole Littman; Michele Callejo; Matthew Martinson; Sarah Galbraith; Ellen R Laird; Barbara J Brandhuber; Guy Vigers; Tony Morales; Rich Woessner; Nikole Randolph; Joseph Lyssikatos; Alan Olivero

doi:10.1016/j.bmcl.2010.12.038

Non-oxime pyrazole based inhibitors of B-Raf kinase

Bioorg Med Chem Lett. 2011 Jun 1;21(11):3488-92. doi: 10.1016/j.bmcl.2010.12.038. Epub 2010 Dec 17.

Authors

Bradley J Newhouse¹, Joshua D Hansen, Jonas Grina, Mike Welch, George Topalov, Nicole Littman, Michele Callejo, Matthew Martinson, Sarah Galbraith, Ellen R Laird, Barbara J Brandhuber, Guy Vigers, Tony Morales, Rich Woessner, Nikole Randolph, Joseph Lyssikatos, Alan Olivero

Affiliation

¹ Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, United States. bnewhouse@arraybiopharma.com

PMID: 21536432
DOI: 10.1016/j.bmcl.2010.12.038

Abstract

The synthesis and biological evaluation of non-oxime pyrazole based B-Raf inhibitors is reported. Several oxime replacements have been prepared and have shown excellent enzyme activity. Further optimization of fused pyrazole 2a led to compound 38, a selective and potent B-Raf inhibitor.

MeSH terms

Animals
Crystallography, X-Ray
Dose-Response Relationship, Drug
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Inhibitory Concentration 50
Mice
Molecular Structure
Oximes / chemistry
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Pyrazoles / chemical synthesis*
Pyrazoles / chemistry
Pyrazoles / pharmacology*

Substances

Enzyme Inhibitors
Oximes
Pyrazoles
pyrazole
Proto-Oncogene Proteins B-raf