RESUMO
This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors.
Assuntos
Amidas/química , Catepsinas/antagonistas & inibidores , Inibidores de Proteases/química , Tiofenos/química , Triazóis/química , Catepsinas/metabolismo , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Ligação Proteica , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacocinética , Triazóis/síntese química , Triazóis/farmacocinéticaRESUMO
The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.
Assuntos
Catepsinas/síntese química , Dipeptídeos/síntese química , Inibidores Enzimáticos/síntese química , Nitrilas/síntese química , Linfócitos B/efeitos dos fármacos , Ligação Competitiva , Catepsinas/química , Catepsinas/farmacologia , Linhagem Celular , Cristalografia por Raios X , Dipeptídeos/química , Dipeptídeos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Modelos Moleculares , Nitrilas/química , Nitrilas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.
RESUMO
The discovery of a series of potent, carboline-based MK2 inhibitors is described. These compounds inhibit MK2 with IC50s as low as 10 nM, as measured in a DELFIA assay. An X-ray crystal structure reveals that they bind in a region near the p-loop and the hinge region of MK2a.
Assuntos
Carbolinas/química , Carbolinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the alpha-carbon of the P1 residue.