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2016 | OriginalPaper | Buchkapitel

Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs

verfasst von : Youla S. Tsantrizos

Erschienen in: Synthesis of Heterocycles in Contemporary Medicinal Chemistry

Verlag: Springer International Publishing

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Abstract

The virally encoded serine protease NS3/NS4A is essential for the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The quest for the discovery of antiviral agents targeting the NS3/NS4A was initiated with a substrate-based hexapeptide as the lead structure. Evaluation of the conformational pre-organization of this ligand to the bioactive conformation led to the design of macrocyclic peptides, typified by the antiviral agents BILN 2061. Today, closely related analogs of BILN 2061 represent an important class of human therapeutics for the treatment of HCV infection. The critical steps in the synthesis of these compounds involves the cyclization of a tripeptide diene, containing a (1R,2S)-vinyl aminocyclopropylcarboxylate residue, via ring-closing metathesis (RCM). Conformational factors, ligand effects, and reaction conditions were evaluated, and a protocol was developed for the efficient production of these peptidomimetics in high yield and diastereomeric purity. The assembly of these challenging molecules and the key optimization studies are described.

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Titel: Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs
verfasst von: Youla S. Tsantrizos
Verlag: Springer International Publishing
Buch: Synthesis of Heterocycles in Contemporary Medicinal Chemistry
Print ISBN: 978-3-319-39915-7

Electronic ISBN: 978-3-319-39917-1

Copyright-Jahr: 2016
DOI: https://doi.org/10.1007/7081_2015_184

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