Discovery and optimization of N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors

Christopher Blackburn; Matthew O Duffey; Alexandra E Gould; Bheemashankar Kulkarni; Jane X Liu; Saurabh Menon; Masayuki Nagayoshi; Tricia J Vos; Juliet Williams

doi:10.1016/j.bmcl.2010.06.110

Discovery and optimization of N-acyl and N-aroylpyrazolines as B-Raf kinase inhibitors

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4795-9. doi: 10.1016/j.bmcl.2010.06.110. Epub 2010 Jun 25.

Authors

Christopher Blackburn¹, Matthew O Duffey, Alexandra E Gould, Bheemashankar Kulkarni, Jane X Liu, Saurabh Menon, Masayuki Nagayoshi, Tricia J Vos, Juliet Williams

Affiliation

¹ Millennium Pharmaceuticals Inc., 40 Landsdowne St., Cambridge MA 01239, United States. [email protected]

PMID: 20630752
DOI: 10.1016/j.bmcl.2010.06.110

Abstract

A high throughput screen identified N-aroylpyrazoline 1 as a selective inhibitor of the V600E mutant of B-Raf kinase. Parallel synthesis of acyl, aroyl, and sulfonyl derivatives led to the identification of several potent inhibitors in both enzymatic and cellular (pERK) assays such as compound 42.

MeSH terms

Amino Acid Substitution
Drug Evaluation, Preclinical
High-Throughput Screening Assays
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrazoles
Pyridines
Recombinant Proteins
Proto-Oncogene Proteins B-raf