RESUMO
An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Imidazóis/química , Compostos de Anilina/química , Animais , Proteínas de Ciclo Celular/química , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Screening of the corporate database led to the discovery of a novel series of N-benzylindole-2-carboxylic acid CCR2b chemokine receptor antagonists. These compounds demonstrate high affinity and functional inhibition of the CCR2b receptor. A discussion of the structure-activity relationships is presented, together with evidence for a highly selective receptor binding profile.
