RESUMEN
The N-2 position of pyridazinone 1, a potent HIV-1 NNRTI that has limited aqueous solubility, was derivatized into a series of hydroxymethyl esters and carbonates as well as one phosphate. The derivatives served as prodrugs to effectively deliver 1 to rat plasma upon oral treatment at 50 mpk. Increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) were observed while the prodrugs and the hydroxymethyl adduct 2 were undetectable.
Asunto(s)
Transcriptasa Inversa del VIH/química , VIH-1/enzimología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Carbonatos/química , Química Farmacéutica/métodos , Diseño de Fármacos , Ésteres/química , Concentración de Iones de Hidrógeno , Modelos Químicos , Profármacos/química , Ratas , SolubilidadRESUMEN
Novel non-nucleoside inhibitors of HIV-RT that contain pyridazinone isosteres were prepared, and a series of triazolinones were found to be potent inhibitors of HIV replication. These compounds were active against several NNRTI-resistant virus strains. Pharmacokinetic studies indicated that inhibitor 7e has good bioavailability in rats. Several fragments of inhibitor 7c were prepared, and the binding of these compounds to HIV-RT was analyzed by surface plasmon resonance spectroscopy.
Asunto(s)
Fármacos Anti-VIH , Piridazinas , Inhibidores de la Transcriptasa Inversa , Triazoles , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Técnicas Químicas Combinatorias , Farmacorresistencia Viral/efectos de los fármacos , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , Triazoles/síntesis química , Triazoles/química , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , Piridazinas , Inhibidores de la Transcriptasa Inversa , Animales , Perros , Farmacorresistencia Viral/efectos de los fármacos , Concentración 50 Inhibidora , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/farmacología , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class.The binding mode maintains the beta13 and beta14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.