RESUMO
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.
Assuntos
Inibidores de Integrase de HIV/química , Integrase de HIV/química , HIV-1/enzimologia , Ácidos Hidroxâmicos/química , Indóis/química , Administração Oral , Animais , Cães , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/toxicidade , Meia-Vida , Hepatócitos/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/toxicidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Naftiridinas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Células Cultivadas , Cães , Desenho de Fármacos , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/farmacologia , HIV-1/enzimologia , Hepatócitos/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Fígado/metabolismo , Conformação Molecular , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.