ABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzodiazepines/therapeutic use , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Humans , Inhibitory Concentration 50 , Mice , Mice, Nude , Models, Molecular , Neovascularization, Pathologic/drug therapy , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Structure-Activity RelationshipABSTRACT
A structure-based focused library approach was employed in an effort to identify more lipophilic replacements for the N-benzylpyroglutamyl group of the VCAM/VLA-4 antagonist 2. This effort led to the discovery of two new classes of potent antagonists characterized by the N-(alpha-phenylcyclopentanoyl- and the N-(2,6-dimethylbenzoyl)-derivatives 60 and 64.
