Conformation-Based Restrictions and Scaffold Replacements in the Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of Deleobuvir (BI 207127)

• Published in: Journal of medicinal chemistry 2014-03, Vol.57 (5), p.1845-1854
• Main Authors: LaPlante, Steven R., Bös, Michael, Brochu, Christian, Chabot, Catherine, Coulombe, René, Gillard, James R., Jakalian, Araz, Poirier, Martin, Rancourt, Jean, Stammers, Timothy, Thavonekham, Bounkham, Beaulieu, Pierre L., Kukolj, George, Tsantrizos, Youla S.
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hepacivirus - drug effects; Hepacivirus - enzymology; Indoles - chemistry; Indoles - pharmacology; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4011862

Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.