RESUMEN
In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay.
Asunto(s)
Antivirales/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/farmacología , Carbamatos , Hepacivirus/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Prolina/análogos & derivados , Prolina/química , Prolina/farmacología , Pirrolidinas , Relación Estructura-Actividad , Valina/análogos & derivados , Proteínas no Estructurales Virales/química , Replicación Viral/efectos de los fármacosRESUMEN
Isonitriles and ureas undergo a condensation reaction in the presence of acid chlorides to give formamidine ureas, for which no general synthetic routes currently exist. A mechanism is proposed in which the key intermediate is an electrophilic adduct of isonitrile and acid chloride. The process is tolerant of moderate variability in the nature of the components, and access to formamidine ureas of varying substitution patterns is further enhanced by a facile exchange reaction with amines. [reaction: see text]