Pyrazolobenzodiazepines: part I. Synthesis and SAR of a potent class of kinase inhibitors.
A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure-activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents.
Liu
Jin-Jun
JJ
Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. jin-jun.liu@roche.com
Daniewski
Irena
I
Ding
Qingjie
Q
Higgins
Brian
B
Ju
Grace
G
Kolinsky
Kenneth
K
Konzelmann
Fred
F
Lukacs
Christine
C
Pizzolato
Giacomo
G
Rossman
Pamela
P
Swain
Amy
A
Thakkar
Kshitij
K
Wei
Chung-Chen
CC
Miklowski
Dorota
D
Yang
Hong
H
Yin
Xuefeng
X
Wovkulich
Peter M
PM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D001569:Benzodiazepines; D051357:Cyclin-Dependent Kinase 2