RESUMEN
Biaryl ethers were recently reported as potent NNRTIs. Herein, we disclose a detailed effort to modify the previously reported compound 1. We have designed and synthesized a series of novel pyrazole derivatives as a surrogate for pyrazolopyridine motif that were potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells.
Asunto(s)
Fármacos Anti-VIH/química , Éteres/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Pirazoles/química , Piridinas/química , Inhibidores de la Transcriptasa Inversa/química , Regulación Alostérica , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Perros , Éteres/síntesis química , Éteres/farmacocinética , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , Humanos , Mutación , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Relación Estructura-ActividadRESUMEN
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key elements of multidrug regimens, called HAART (Highly Active Antiretroviral Therapy), that are used to treat HIV-1 infections. Elucidation of the structure-activity relationships of the thiocarbamate moiety of the previous published lead compound 2 provided a series of novel tetrahydroquinoline derivatives as potent inhibitors of HIV-1 RT with nanomolar intrinsic activity on the WT and key mutant enzymes and potent antiviral activity in infected cells. The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described.
Asunto(s)
Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Quinolinas/química , Inhibidores de la Transcriptasa Inversa/química , Sitio Alostérico , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Sitios de Unión , Cristalografía por Rayos X , Transcriptasa Inversa del VIH/metabolismo , Conformación Molecular , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/metabolismo , Quinolinas/síntesis química , Quinolinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Tiocarbamatos/química , Tiocarbamatos/farmacologíaRESUMEN
Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound also exhibited a clean safety profile in preclinical safety studies.