Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors.
Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. gopalsa@wyeth.com
Ciszewski
Greg
G
Shi
Mengxiao
M
Berger
Dan
D
Hu
Yongbo
Y
Lee
Frederick
F
Feldberg
Larry
L
Frommer
Eileen
E
Kim
Steven
S
Collins
Karen
K
Wojciechowicz
Donald
D
Mallon
Robert
R
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine; D048493:Proto-Oncogene Proteins B-raf