Discovery and optimization of pyrazoline compounds as B-Raf inhibitors

Matthew O Duffey; Ruth Adams; Christopher Blackburn; Ryan W Chau; Susan Chen; Katherine M Galvin; Khristofer Garcia; Alexandra E Gould; Paul D Greenspan; Sean Harrison; Shih-Chung Huang; Mi-Sook Kim; Bheemashankar Kulkarni; Steven Langston; Jane X Liu; Li-Ting Ma; Saurabh Menon; Masayuki Nagayoshi; R Scott Rowland; Tricia J Vos; Tianlin Xu; Johnny J Yang; Shaoxia Yu; Qin Zhang

doi:10.1016/j.bmcl.2010.06.113

Discovery and optimization of pyrazoline compounds as B-Raf inhibitors

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4800-4. doi: 10.1016/j.bmcl.2010.06.113. Epub 2010 Jun 25.

Affiliation

¹ Millennium Pharmaceuticals, Inc., Oncology, Medicinal Chemistry, 40 Landsdowne St., Cambridge, MA 02139, United States. matthew.duffey@mpi.com

PMID: 20634068
DOI: 10.1016/j.bmcl.2010.06.113

Abstract

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.

MeSH terms

Amino Acid Substitution
Binding Sites
Computer Simulation
Drug Evaluation, Preclinical
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
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Structure-Activity Relationship

Substances

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