RESUMEN
Resulting from a vHTS based on a pharmacophore alignment on known ß3-adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human ß3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hß1- and hß2-adrenoceptors and a promising safety profile.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 3/química , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3/síntesis química , Línea Celular , Supervivencia Celular , Diseño de Fármacos , Humanos , Unión Proteica , Pirimidinas/síntesis químicaRESUMEN
Peptide-semicarbazones derived from Z-Trp-Trp-Phe-aldehyde inhibit the chymotryptic activity of the human proteasome at nanomolar concentrations, but are less active in a NFkappaB reporter gene assay. Cyclic semicarbazones, in contrast, combine a strong inhibitory effect on the enzyme with an inhibition of NFkappaB signaling in the nanomolar range. In addition, a practical synthesis for scale-up of such compounds was developed.
Asunto(s)
Péptidos/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma , Semicarbazonas/síntesis química , Semicarbazonas/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Inmunosupresores/farmacología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , FN-kappa B/metabolismo , Inhibidores de Proteasas/química , Complejo de la Endopetidasa Proteasomal/química , Semicarbazonas/química , Sensibilidad y Especificidad , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Toll-like receptor (TLR)-mediated signaling is proposed as an immunotherapeutic target against tumorigenesis. Natural killer (NK) cells play a critical role in host defense against tumors. Specifically, formation of tumor metastasis in various organs can be suppressed by the local activity of NK cells. In this study, we present a novel TLR7 agonist (termed SC-1) that induces pro-inflammatory cytokines in human blood cells, activates NK cell function, and is highly efficient in preventing lung metastases in a pulmonary metastatic Renca model. Furthermore, a second compound (termed SC-2), acting as dual-specific TLR7 and TLR8 agonist, was evaluated with respect to its immunostimulatory and NK cell-activating capacities. The release of pro-inflammatory cytokines was shown to be even more pronounced with this compound. Additional experiments showed a significant up-regulation of activation marker CD69 on NK cells and increased cytolytic activity of peripheral blood cells compared to the effect of a monospecific TLR7 agonist SC-1. Normally, TLR7 and TLR8 are expressed on different immune cell subpopulations. TLR7 expression on antigen-presenting cells is detected in plasmacytoid dendritic cells, CD34+-derived dendritic cells, and B-cells, whereas TLR8 is mainly expressed on cells of the myeloid lineage, such as monocytes, macrophages, and myeloid dendritic cells. Therefore, a compound that activates both TLR7 and TLR8 would result in a highly efficient immune system activation and may give rise to an enhanced anti-tumor activity in vivo compared to that elicited by a monospecific TLR7 agonist.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Activación de Linfocitos/efectos de los fármacos , Glicoproteínas de Membrana/agonistas , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Animales , Anticuerpos Monoclonales Humanizados , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inmunoterapia , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Lectinas Tipo C , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 8/metabolismoRESUMEN
A novel class of NF-kappaB pathway signaling inhibitors was discovered by virtual screening, medicinal chemistry, and QSAR analysis. An initial set of compounds inhibited NF-kappaB signaling in a whole cell reporter gene assay in the micro-molar range. Activity was improved step by step by medicinal chemistry to yield nano-molar signaling inhibitors.