RESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Benzodiazepinas/uso terapêutico , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Modelos Moleculares , Neovascularização Patológica/tratamento farmacológico , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Relação Estrutura-AtividadeRESUMO
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.