RESUMEN
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.
Asunto(s)
Inhibidores de Integrasa VIH/síntesis química , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Naftiridinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Células Cultivadas , Perros , Diseño de Fármacos , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/enzimología , Hepatocitos/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Hígado/metabolismo , Conformación Molecular , Naftiridinas/farmacocinética , Naftiridinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.