Structure-Based Macrocyclization Yields Hepatitis C Virus NS5B Inhibitors with Improved Binding Affinities and Pharmacokinetic Properties (pages 4637–4640)
Dr. Maxwell D. Cummings, Dr. Tse-I Lin, Lili Hu, Dr. Abdellah Tahri, David McGowan, Dr. Katie Amssoms, Stefaan Last, Dr. Benoit Devogelaere, Marie-Claude Rouan, Dr. Leen Vijgen, Dr. Jan Martin Berke, Pascale Dehertogh, Els Fransen, Erna Cleiren, Liesbet van der Helm, Dr. Gregory Fanning, Dr. Kristof Van Emelen, Prof. Dr. Origène Nyanguile, Dr. Kenny Simmen, Dr. Pierre Raboisson and Dr. Sandrine Vendeville
Version of Record online: 30 MAR 2012 | DOI: 10.1002/anie.201200110
The concept of drug-likeness distills the physicochemical properties of small-molecule drugs to a set of rules. Macrocyclic drugs are known to break these rules. A structure-based macrocyclization strategy was applied to design new hepatitis C virus NS5B inhibitors with improved pharmacokinetic properties, exemplifying a rational strategy for overcoming the confines of standard “drug-like chemical space”.