RESUMEN
A research program to discover solubilizing prodrugs of the HCV NS5A inhibitor pibrentasvir (PIB) identified phosphomethyl analog 2 and trimethyl-lock (TML) prodrug 9. The prodrug moiety is attached to a benzimidazole nitrogen atom via an oxymethyl linkage to allow for rapid and complete release of the drug for absorption following phosphate removal by intestinal alkaline phosphatase. These prodrugs have good hydrolytic stability properties and improved solubility compared to PIB, both in aqueous buffer (pH 7) and FESSIF (pH 5). TML prodrug 9 provided superior in vivo performance, delivering high plasma concentrations of PIB in PK studies conducted in mice, dogs, and monkeys. The improved dissolution properties of these phosphate prodrugs provide them the potential to simplify drug dosage forms for PIB-containing HCV therapy.
Asunto(s)
Antivirales/química , Bencimidazoles/química , Profármacos/química , Pirrolidinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Área Bajo la Curva , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Perros , Ratones , Profármacos/farmacología , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , SolubilidadRESUMEN
A one-pot procedure for the synthesis of unsymmetrical ketones utilizing a pyrrole-bearing carbonyl linchpin reagent (carbonyl linchpin N,O-dimethylhydroxylamine pyrrole; CLAmP) is reported. In contrast to other carbonyl dielectrophile equivalents, CLAmP enables the synthesis of ketones from a variety of organolithium and Grignard reagents. The electrophilic nature of CLAmP enables the addition of less reactive as well as thermally unstable nucleophiles. CLAmP was designed to form kinetically stable tetrahedral intermediates upon the addition of organometallic nucleophiles. Evidence for the existence of persistent tetrahedral intermediates was obtained through inâ situ IR studies.
Asunto(s)
Alcaloides/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Lycopodium/química , Alcaloides/química , Catálisis , Compuestos Heterocíclicos de 4 o más Anillos/química , Oxidación-Reducción , Piridinas/química , Compuestos de Selenio/química , Óxidos de Selenio , EstereoisomerismoRESUMEN
The surface-enhanced Raman scattering (SERS) activity of nanoporous gold (NPG) can be boosted by controlled surface passivation. The SERS activities of unfunctionalized NPG were first optimized by etching substrates with NaI/I(2) (triiodide) and using 2-mercaptopyridine (2-MP) as the probing analyte. Gains in analyte sensitivity were then achieved by passivating the superficial regions of the NPG substrates with dimethyldithiocarbamate (Me(2)DTC) while leaving the more recessed "hot spots" available for SERS detection. Partial surface passivation with DTCs increased the substrate sensitivity to chemisorptive analytes such as 2-MP by an order of magnitude, whereas surface saturation lowered the sensitivity by an order of magnitude. The partially passivated NPG films can also be functionalized with supramolecular receptors for chemoselective SERS. Installation of a DTC-anchored terpyridine enabled the detection of divalent metal ions at trace levels, as determined by the complexation-induced shift of a characteristic Raman peak of the metal ion receptor.