title: Discovery and optimization of pyrazoline compounds as B-Raf inhibitors.
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.
authors.affiliation: Millennium Pharmaceuticals, Inc., Oncology, Medicinal Chemistry, 40 Landsdowne St., Cambridge, MA 02139, United States. matthew.duffey@mpi.com
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Duffey
authors.forename: Ruth
authors.initials: R
authors.lastname: Adams
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Chau
authors.forename: Susan
authors.initials: S
authors.lastname: Chen
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Galvin
authors.forename: Khristofer
authors.initials: K
authors.lastname: Garcia
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gould
authors.forename: Paul D
authors.initials: PD
authors.lastname: Greenspan
authors.forename: Sean
authors.initials: S
authors.lastname: Harrison
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Huang
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.forename: Bheemashankar
authors.initials: B
authors.lastname: Kulkarni
authors.forename: Steven
authors.initials: S
authors.lastname: Langston
authors.forename: Jane X
authors.initials: JX
authors.lastname: Liu
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Ma
authors.forename: Saurabh
authors.initials: S
authors.lastname: Menon
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagayoshi
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rowland
authors.forename: Tricia J
authors.initials: TJ
authors.lastname: Vos
authors.forename: Tianlin
authors.initials: T
authors.lastname: Xu
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Yu
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D048493:Proto-Oncogene Proteins B-raf