Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors.
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. bergerd@wyeth.com
Dan M
DM
Berger
Nancy
N
Torres
Minu
M
Dutia
Dennis
D
Powell
Greg
G
Ciszewski
Ariamala
A
Gopalsamy
Jeremy I
JI
Levin
Kyung-Hee
KH
Kim
Weixin
W
Xu
James
J
Wilhelm
YongBo
Y
Hu
Karen
K
Collins
Larry
L
Feldberg
Steven
S
Kim
Eileen
E
Frommer
Donald
D
Wojciechowicz
Robert
R
Mallon
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D048493:Proto-Oncogene Proteins B-raf