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.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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