Novel pyrazolopyrimidines as highly potent B-Raf inhibitors.
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
Di Grandi
Martin J
MJ
Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. digranm@pfizer.com
Berger
Dan M
DM
Hopper
Darrin W
DW
Zhang
Chunchun
C
Dutia
Minu
M
Dunnick
Alejandro L
AL
Torres
Nancy
N
Levin
Jeremy I
JI
Diamantidis
George
G
Zapf
Christoph W
CW
Bloom
Jonathan D
JD
Hu
YongBo
Y
Powell
Dennis
D
Wojciechowicz
Donald
D
Collins
Karen
K
Frommer
Eileen
E
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C447480:pyrazolo(3,4-b)pyridine; D048493:Proto-Oncogene Proteins B-raf