RESUMO
A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.
Assuntos
Antivirais/química , Hepacivirus/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Hepatite C/virologia , Humanos , Mutação , Pargilina/química , Pirazinas/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
[reaction: see text] The first total synthesis of 5,6,11-trideoxytetrodotoxin (1) and its 4-epimer were achieved. The synthesis is characterized by the stereoselective construction of the quaternary amino carbon center at C8a by an asymmetric transferring Strecker synthesis and the highly efficient conversion of cyanohydrin 4 to 1 via intramolecular cyclization reactions.