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 selected inhibitors is also reported.
Duffey
Matthew O
MO
Millennium Pharmaceuticals, Inc., Oncology, Medicinal Chemistry, 40 Landsdowne St., Cambridge, MA 02139, United States. matthew.duffey@mpi.com
Adams
Ruth
R
Blackburn
Christopher
C
Chau
Ryan W
RW
Chen
Susan
S
Galvin
Katherine M
KM
Garcia
Khristofer
K
Gould
Alexandra E
AE
Greenspan
Paul D
PD
Harrison
Sean
S
Huang
Shih-Chung
SC
Kim
Mi-Sook
MS
Kulkarni
Bheemashankar
B
Langston
Steven
S
Liu
Jane X
JX
Ma
Li-Ting
LT
Menon
Saurabh
S
Nagayoshi
Masayuki
M
Rowland
R Scott
RS
Vos
Tricia J
TJ
Xu
Tianlin
T
Yang
Johnny J
JJ
Yu
Shaoxia
S
Zhang
Qin
Q
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
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011994:Recombinant Proteins; D048493:Proto-Oncogene Proteins B-raf