RESUMO
The design and synthesis of a new class of p38alpha MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38alpha enzymatic and cell-based cytokine TNFalpha production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.
Assuntos
Amidas/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Oxalatos/química , Piperidinas/química , Amidas/metabolismo , Amidas/farmacologia , Cristalografia por Raios X , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/farmacologia , Humanos , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Oxalatos/metabolismo , Oxalatos/farmacologia , Piperidinas/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piperazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Animais , Cães , Haplorrinos , Humanos , Indóis/farmacocinética , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Piperazina , Piperazinas/farmacocinética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Secundária de Proteína , RatosRESUMO
p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors.