RESUMO
A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Piperidinas/síntese química , Receptores CCR2/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Asma/tratamento farmacológico , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Piperidinas/química , Piperidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Receptores CCR2/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.