RESUMEN
Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.
Asunto(s)
Amidas/farmacología , Artritis/tratamiento farmacológico , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Administración Oral , Amidas/administración & dosificación , Amidas/química , Animales , Artritis/inducido químicamente , Diferenciación Celular/efectos de los fármacos , Colágeno , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Relación Estructura-Actividad , Células Th17RESUMEN
BACKGROUND: Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T- and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions remains elusive. OBJECTIVE: It was shown recently that proinflammatory or anti-inflammatory effector functions of IgG molecules are determined by different Fc N-linked glycosylation patterns. We sought to examine the Fc glycosylation and anti-inflammatory quality of IgG molecules formed on TD tolerance induction. METHODS: We administered chicken ovalbumin (OVA) with or without costimulus to mice and analyzed OVA-reactive IgG Fc glycosylation. The anti-inflammatory function of differentially glycosylated anti-OVA IgGs was further investigated in studies with dendritic cell cultures and in an in vivo model of allergic airway disease. Additionally, we analyzed the Fc glycosylation pattern of birch pollen-reactive serum IgGs after successful allergen-specific immunotherapy in patients. RESULTS: Stimulation with TD antigens under inflammatory conditions induces plasma cells expressing low levels of α2,6-sialyltransferase and producing desialylated IgGs. In contrast, plasma cells induced on tolerance induction did not downregulate α2,6-sialyltransferase expression and secreted immunosuppressive sialylated IgGs that were sufficient to block antigen-specific T- and B-cell responses, dendritic cell maturation, and allergic airway inflammation. Importantly, successful specific immunotherapy in allergic patients also induced sialylated allergen-specific IgGs. CONCLUSIONS: Our data show a novel antigen-specific immunoregulatory mechanism mediated by anti-inflammatory sialylated IgGs that are formed on TD tolerance induction. These findings might help to develop novel antigen-specific therapies for the treatment of allergy and autoimmunity.
Asunto(s)
Antígenos/inmunología , Tolerancia Inmunológica/inmunología , Inmunoglobulina G/inmunología , Linfocitos T/inmunología , Animales , Complejo Antígeno-Anticuerpo/inmunología , Desensibilización Inmunológica , Epítopos/inmunología , Femenino , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Receptores de IgG/metabolismo , Sialiltransferasas/biosíntesis , beta-D-Galactósido alfa 2-6-SialiltransferasaRESUMEN
A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists.