RESUMEN
In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.
Asunto(s)
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacología , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , 6-Aminonicotinamida/síntesis química , 6-Aminonicotinamida/uso terapéutico , Animales , Rechazo de Injerto/prevención & control , Trasplante de Corazón , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/uso terapéutico , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , RatasRESUMEN
Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.
Asunto(s)
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacología , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Citocromo P-450 CYP3A/metabolismo , Agonismo Inverso de Drogas , Receptores de Ghrelina/agonistas , 6-Aminonicotinamida/metabolismo , Fármacos Antiobesidad/metabolismo , Descubrimiento de Drogas , Humanos , Microsomas Hepáticos/metabolismo , Obesidad/tratamiento farmacológico , Receptores de Ghrelina/metabolismoRESUMEN
This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.