Indazolylpyrazolopyrimidine as highly potent B-Raf inhibitors with in vivo activity.
Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
Wang
Xiaolun
X
Pfizer Global Research and Development, 401 N Middletown Road, Pearl River, New York 10965, United States. xxw104@gmail.com
Berger
Dan M
DM
Salaski
Edward J
EJ
Torres
Nancy
N
Dutia
Minu
M
Hanna
Cilien
C
Hu
Yongbo
Y
Levin
Jeremy I
JI
Powell
Dennis
D
Wojciechowicz
Donald
D
Collins
Karen
K
Frommer
Eileen
E
Lucas
Judy
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C554425:7-(2,6-difluoro-4-(5-methyl-2,5-diazabicyclo(2.2.1)heptan-2-yl)phenyl)-3-(1H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo(1,5-a)pyrimidine; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007191:Indazoles; D011720:Pyrazoles; D011743:Pyrimidines; D048493:Proto-Oncogene Proteins B-raf