RESUMO
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
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.
