Structure-Based Macrocyclization Yields Hepatitis C Virus NS5B Inhibitors with Improved Binding Affinities and Pharmacokinetic Properties

• Published in: Angewandte Chemie (International ed.) Vol. 51; no. 19; pp. 4637 - 4640
• Main Authors: Cummings, Maxwell D., Lin, Tse-I, Hu, Lili, Tahri, Abdellah, McGowan, David, Amssoms, Katie, Last, Stefaan, Devogelaere, Benoit, Rouan, Marie-Claude, Vijgen, Leen, Berke, Jan Martin, Dehertogh, Pascale, Fransen, Els, Cleiren, Erna, van der Helm, Liesbet, Fanning, Gregory, Van Emelen, Kristof, Nyanguile, Origène, Simmen, Kenny, Raboisson, Pierre, Vendeville, Sandrine
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.05.2012; WILEY‐VCH Verlag; Wiley
• Subjects: Administration, Oral; Animals; Binding Sites; Chemistry; Chemistry, Multidisciplinary; Crystallography, X-Ray; Cyclization; Dogs; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Hepacivirus - metabolism; hepatitis C virus; Indoles - chemistry; inhibitors; macrocycles; Male; pharmacokinetics; Physical Sciences; polymerases; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Science & Technology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; inhibitors; MEMBRANE-PERMEABILITY; polymerases; REACTIVITY; POTENT INHIBITORS; ALLOSTERIC INHIBITORS; DISCOVERY; macrocycles; hepatitis C virus; pharmacokinetics; OPTIMIZATION; PROTEASE; RNA-POLYMERASE
• ISSN: 1433-7851; 1521-3773
• 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”.