RESUMEN
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.
RESUMEN
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.
Asunto(s)
Amidas/química , Catepsinas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Tiofenos/química , Triazoles/química , Catepsinas/metabolismo , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/farmacocinética , Triazoles/síntesis química , Triazoles/farmacocinéticaRESUMEN
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.
Asunto(s)
Carbolinas/química , Carbolinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Química Farmacéutica/métodos , Nitrilos/química , Dominio Catalítico , Dipéptidos/química , Diseño de Fármacos , Humanos , Modelos Químicos , Conformación Molecular , Nitrilos/clasificación , Péptidos/química , Piperidinas/química , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
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.