RESUMEN
We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.
Asunto(s)
Canal de Potasio ERG1/metabolismo , VIH-1/fisiología , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Cetonas/química , Animales , Perros , Evaluación Preclínica de Medicamentos , Semivida , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/antagonistas & inhibidores , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Humanos , Imidazoles/química , Oxazoles/química , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Relación Estructura-Actividad , Activación Viral/efectos de los fármacosRESUMEN
Structure- and ligand-based virtual-screening methods (docking, 2D- and 3D-similarity searching) were analyzed for their effectiveness in virtual screening against FFAR2. To evaluate the performance of these methods, retrospective virtual screening was performed. Statistical quality of the methods was evaluated by BEDROC and RIE. The results revealed that electrostatic similarity search protocol using EON (ET combo) outperformed all other protocols with outstanding enrichment of >95% in top 1% and 2% of the dataset with an AUC of 0.958. Interestingly, the hit lists that are obtained from different virtual-screening methods are generally highly complementary to hits found from electrostatic similarity searching. These results suggest that considering electrostatic similarity searching first increases the chance of identifying more (and more diverse) active compounds from a virtual-screening campaign. Accordingly, prospective virtual screening using electrostatic similarity searching was used to identify novel FFAR2 ligands. The discovered compounds provide new chemical matter starting points for the initiation of a medicinal chemistry campaign.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Receptores de Superficie Celular/agonistas , Antiinflamatorios no Esteroideos/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Lysophosphatidic acid (LPA) is a growth factor-like mediator and a ligand for multiple GPCR. The LPA2 GPCR mediates antiapoptotic and mucosal barrier-protective effects in the gut. We synthesized sulfamoyl benzoic acid (SBA) analogues that are the first specific agonists of LPA2, some with subnanomolar activity. We developed an experimental SAR that is supported and rationalized by computational docking analysis of the SBA compounds into the LPA2 ligand-binding pocket.