RESUMEN
The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.
Asunto(s)
Adenosina/farmacología , Enfermedades Autoinmunes/prevención & control , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inflamación/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Adenosina/química , Adenosina/metabolismo , Animales , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I/química , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Transgénicos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Quinolinas/química , Quinolinas/metabolismo , Ratas Endogámicas Lew , Células Sf9 , Relación Estructura-ActividadRESUMEN
Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.
Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Modelos MolecularesRESUMEN
The natural product prodigiosin 1, often described as an H+/Cl- symport cotransporter, can transport Cl- across lipid vesicles via an anion exchange (or antiport) mechanism.