RESUMEN
Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.
Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/enzimología , Indoles/farmacología , Ácidos Fosfínicos/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Línea Celular , Cristalografía por Rayos X , Perros , Relación Dosis-Respuesta a Droga , Transcriptasa Inversa del VIH/metabolismo , Hepatocitos/química , Hepatocitos/metabolismo , Humanos , Indoles/síntesis química , Indoles/química , Macaca fascicularis , Masculino , Modelos Moleculares , Estructura Molecular , Ácidos Fosfínicos/síntesis química , Ácidos Fosfínicos/química , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-ActividadRESUMEN
A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in the reverse transcriptase gene. Chiral separation of the enantiomers showed that only R enantiomer retained the activity. The pharmacokinetic, solubility, and metabolic properties of 14 were assessed.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/metabolismo , Indoles/síntesis química , Ácidos Fosfínicos/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Animales , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Línea Celular , Perros , Farmacorresistencia Viral , Transcriptasa Inversa del VIH/genética , Haplorrinos , Hepatocitos/metabolismo , Humanos , Indoles/farmacocinética , Indoles/farmacología , Modelos Moleculares , Mutación , Ácidos Fosfínicos/farmacocinética , Ácidos Fosfínicos/farmacología , Ratas , Inhibidores de la Transcriptasa Inversa/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacología , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Several thieno[3,4-d]pyrimidine derivatives, including four hitherto unknown 2',3'-dideoxy- and 2',3'-dideoxy-2',3'-didehydro-C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity.
