RESUMEN
[structures: see text] Tripeptide dienes containing an (1R,2S)-vinyl aminocyclopropylcarboxylate residue were cyclized to beta-strand scaffolds under ring-closing metathesis (RCM). Conformational factors, ligand effects, and reaction conditions were evaluated. A protocol was developed for the efficient synthesis of 15-membered ring peptides in high diastereomeric purity. These peptides are key synthetic precursors to antiviral agents that target the hepatitis C virus and represent the first class of clinically validated pharmaceutical agents that are synthesized in large scale using RCM.
Asunto(s)
Oligopéptidos/química , Propano/análogos & derivados , Catálisis , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , EstereoisomerismoAsunto(s)
Bencimidazoles/química , Hepacivirus/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring beta-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.
Asunto(s)
Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitios de Unión , Diseño de Fármacos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Imitación Molecular , Inhibidores de Proteasas/químicaRESUMEN
The synthesis of BILN 2061, an NS3 protease inhibitor with proven antiviral effect in humans, was accomplished in a convergent manner from four building blocks. The procedure described here was suitable for the preparation of multigram quantities of BILN 2061 for preclinical pharmacological evaluation.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Carbamatos/química , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Humanos , Compuestos Macrocíclicos/química , Estructura Molecular , Inhibidores de Proteasas/química , Quinolinas/química , Tiazoles/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.