Discovery and optimization of pyrazoline compounds as B-Raf inhibitors

The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of se...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (16), p.4800-4804
Main Authors: Duffey, Matthew O., Adams, Ruth, Blackburn, Christopher, Chau, Ryan W., Chen, Susan, Galvin, Katherine M., Garcia, Khristofer, Gould, Alexandra E., Greenspan, Paul D., Harrison, Sean, Huang, Shih-Chung, Kim, Mi-Sook, Kulkarni, Bheemashankar, Langston, Steven, Liu, Jane X., Ma, Li-Ting, Menon, Saurabh, Nagayoshi, Masayuki, Rowland, R. Scott, Vos, Tricia J., Xu, Tianlin, Yang, Johnny J., Yu, Shaoxia, Zhang, Qin
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Antineoplastic agents
B-Raf
B-Raf inhibitor
Binding Sites
Biological and medical sciences
Computer Simulation
Drug Evaluation, Preclinical
General aspects
Medical sciences
Pharmacology. Drug treatments
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 - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoline
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Structure-Activity Relationship
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Summary:The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.06.113