Non-oxime inhibitors of B-Raf(V600E) kinase

Li Ren; Steve Wenglowsky; Greg Miknis; Bryson Rast; Alex J Buckmelter; Robert J Ely; Stephen Schlachter; Ellen R Laird; Nikole Randolph; Michele Callejo; Matthew Martinson; Sarah Galbraith; Barbara J Brandhuber; Guy Vigers; Tony Morales; Walter C Voegtli; Joseph Lyssikatos

doi:10.1016/j.bmcl.2010.12.061

Non-oxime inhibitors of B-Raf(V600E) kinase

Bioorg Med Chem Lett. 2011 Feb 15;21(4):1243-7. doi: 10.1016/j.bmcl.2010.12.061. Epub 2010 Dec 19.

Authors

Li Ren¹, Steve Wenglowsky, Greg Miknis, Bryson Rast, Alex J Buckmelter, Robert J Ely, Stephen Schlachter, Ellen R Laird, Nikole Randolph, Michele Callejo, Matthew Martinson, Sarah Galbraith, Barbara J Brandhuber, Guy Vigers, Tony Morales, Walter C Voegtli, Joseph Lyssikatos

Affiliation

¹ Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA.

PMID: 21251822
DOI: 10.1016/j.bmcl.2010.12.061

Abstract

The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.

MeSH terms

Amino Acid Substitution
Animals
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
Humans
Indazoles / chemistry
Mice
Microsomes, Liver / metabolism
Mutation
Oximes / chemistry
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
Pyrazoles / chemistry
Structure-Activity Relationship

Substances

Indazoles
Oximes
Protein Kinase Inhibitors
Pyrazoles
Proto-Oncogene Proteins B-raf