RESUMEN
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.
Asunto(s)
Antivirales/síntesis química , Carbamatos/síntesis química , Hepacivirus/enzimología , Compuestos Heterocíclicos/síntesis química , Inhibidores de Proteasas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/química , Antivirales/farmacología , Disponibilidad Biológica , Carbamatos/química , Carbamatos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Inyecciones Intravenosas , Prolina/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
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/metabolismoAsunto(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
[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 , EstereoisomerismoRESUMEN
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.