RESUMEN
HIV-1 integrase 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 discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the ß-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series.
Asunto(s)
Inhibidores de Integrasa VIH/química , Integrasa de VIH/química , VIH-1/enzimología , Ácidos Hidroxámicos/química , Indoles/química , Administración Oral , Animales , Perros , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/toxicidad , Semivida , Hepatocitos/efectos de los fármacos , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/toxicidad , Relación Estructura-ActividadRESUMEN
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
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.