RESUMEN
Effective therapeutic agents are highly desired for immune-mediated allergic diseases. Herein, we report the design, synthesis, and structure-activity relationship of an o-aminopyridinyl alkyne series as novel orally bioavailable antiallergic agents, which was identified through phenotypic screening. Compound optimization yielded a highly potent compound 36, which effectively suppressed mast cell degranulation in a dose-dependent manner (IC50, 2.54 nM for RBL-2H3 cells; 48.28 nM for peritoneal mast cells (PMCs)) with a good therapeutic index. It also regulated the activation of FcεRI-mediated downstream signaling proteins in IgE/Ag-stimulated RBL-2H3 cells. In addition, 36 exhibited excellent in vivo pharmacokinetic properties and antiallergic efficacy in both passive systemic anaphylaxis (PSA) and house dust mite (HDM)-induced murine models of pulmonary allergic inflammation. Furthermore, preliminary analysis of the kinases profile identified Src-family kinases as potential targets for 36. Compound 36 may serve as a new valuable lead compound for future antiallergic drug discovery.
Asunto(s)
Alquinos/uso terapéutico , Aminopiridinas/uso terapéutico , Antialérgicos/uso terapéutico , Inflamación/tratamiento farmacológico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Alquinos/síntesis química , Alquinos/farmacocinética , Aminopiridinas/síntesis química , Aminopiridinas/farmacocinética , Animales , Antialérgicos/síntesis química , Antialérgicos/farmacocinética , Degranulación de la Célula/efectos de los fármacos , Línea Celular Tumoral , Diseño de Fármacos , Femenino , Mastocitos/efectos de los fármacos , Ratones Endogámicos BALB C , Estructura Molecular , Ratas , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-ActividadRESUMEN
An efficient, ecofriendly, amide-functionalized cellulose-based porous adsorbent was synthesized by a cross-linking reaction between cellulose filament fibers and bisacrylamide at room temperature. This process is simple, fast and inexpensive, and has significant potential for industrial applications. The prepared material has numerous adsorption sites, resulting in the highly efficient removal of anionic dyes and copper ions from aqueous media. The maximum adsorption capacities of this cellulose-based adsorbent for the dyes Acid Black 1 and Acid Red 18 and for copper ions were 751.8, 417.9, and 51.3â¯mgâ¯g-1, respectively. Regeneration experiments showed that the removal efficiencies for all model pollutants remained above 92 % after five consecutive recycling trials. These results indicate that amide-functionalized cellulose-based adsorbents could possibly be used to treat industrial wastewaters.