RESUMEN
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.
Asunto(s)
Aminopiridinas/farmacología , Anemia/tratamiento farmacológico , Hepcidinas/antagonistas & inhibidores , Quinazolinas/farmacología , Administración Oral , Aminopiridinas/administración & dosificación , Aminopiridinas/síntesis química , Aminopiridinas/farmacocinética , Anemia/etiología , Animales , Sitios de Unión , Línea Celular Tumoral , Diseño de Fármacos , Hepcidinas/sangre , Hepcidinas/química , Humanos , Inflamación/inducido químicamente , Inflamación/complicaciones , Interleucina-6/metabolismo , Hierro/metabolismo , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Quinazolinas/administración & dosificación , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Relación Estructura-ActividadRESUMEN
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure-activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Descubrimiento de Drogas , Hepcidinas/antagonistas & inhibidores , Indazoles/farmacología , Inflamación/tratamiento farmacológico , Pirazoles/farmacología , Lesión Pulmonar Aguda/inducido químicamente , Administración Oral , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Hep G2 , Hepcidinas/biosíntesis , Humanos , Indazoles/administración & dosificación , Indazoles/química , Inflamación/inducido químicamente , Interleucina-6 , Ratones , Estructura Molecular , Pirazoles/administración & dosificación , Pirazoles/química , Relación Estructura-ActividadRESUMEN
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Carbamatos/química , Carbamatos/farmacología , Hepcidinas/antagonistas & inhibidores , Administración Oral , Animales , Benzoxazoles/administración & dosificación , Benzoxazoles/farmacocinética , Carbamatos/administración & dosificación , Carbamatos/farmacocinética , Regulación de la Expresión Génica/efectos de los fármacos , Semivida , Hepcidinas/genética , Hepcidinas/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Concentración 50 Inhibidora , Interleucina-6 , Maleatos/administración & dosificación , Maleatos/química , Maleatos/farmacocinética , Maleatos/farmacología , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Animales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , Relación Estructura-ActividadRESUMEN
Psoriasis is a common inflammatory skin disease that affects approximately 1% of the population worldwide. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene polymorphisms have been strongly associated with psoriasis susceptibility. In this study, we investigate how TNFAIP3, also known as A20, may regulate psoriasis susceptibility. We found that haplo-insufficient A20+/- mice develop severe toll-like receptor (TLR)-induced skin inflammation compared to wild type mice owing to amplified production of interleukin (IL)-17 and IL-23. Examination of TNFAIP3 mRNA expression in skin biopsies from patients with psoriasis revealed reduced expression in both involved and uninvolved skin. Our results demonstrate the clinical importance of reduced dermal expression of A20 in psoriasis and suggest that A20 restriction of the IL-23/17 axis protects against psoriasis.