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

• Published in: Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (16), p.4795-4799
• Main Authors: Blackburn, Christopher, Duffey, Matthew O., Gould, Alexandra E., Kulkarni, Bheemashankar, Liu, Jane X., Menon, Saurabh, Nagayoshi, Masayuki, Vos, Tricia J., Williams, Juliet
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Antineoplastic agents; B-Raf inhibitor; Biological and medical sciences; Drug Evaluation, Preclinical; General aspects; High-Throughput Screening Assays; Medical sciences; Parallel synthesis; Pharmacology. Drug treatments; 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; Pyrazoline; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.06.110

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. 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.