RESUMEN
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/síntesis química , Antivirales/síntesis química , Compuestos Organofosforados/síntesis química , Adenosina/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antivirales/farmacología , Línea Celular , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Nucleótidos/síntesis química , Nucleótidos/farmacología , Compuestos Organofosforados/farmacología , Relación Estructura-ActividadAsunto(s)
Anticonvulsivantes/efectos adversos , Corea/inducido químicamente , Lateralidad Funcional/fisiología , Ácido Valproico/efectos adversos , Encéfalo/patología , Corea/diagnóstico , Epilepsia/tratamiento farmacológico , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana EdadRESUMEN
Paroxysmal autonomic instability with dystonia, an under-recognized and poorly understood phenomenon of episodic central dysautonomia is associated with various cerebral insults. Treatment options include benzodiazepines, opioids, and gabapentin. Using an illustrative case, we discuss presentation, pathomechanisms, and management of this condition.