RESUMO
[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.
Assuntos
Oligopeptídeos/química , Propano/análogos & derivados , Catálise , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , EstereoisomerismoAssuntos
Benzimidazóis/química , Hepacivirus/enzimologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Benzimidazóis/farmacologia , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítios de Ligação , Desenho de Fármacos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Mimetismo Molecular , Inibidores de Proteases/químicaRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Carbamatos/química , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Humanos , Compostos Macrocíclicos/química , Estrutura Molecular , Inibidores de Proteases/química , Quinolinas/química , Tiazóis/química , Proteínas não Estruturais Virais/metabolismoRESUMO
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.
