| Literature DB >> 24195700 |
Francisco X Talamas1, Sarah C Abbot, Shalini Anand, Ken A Brameld, David S Carter, Jun Chen, Dana Davis, Javier de Vicente, Amy D Fung, Leyi Gong, Seth F Harris, Petra Inbar, Sharada S Labadie, Eun K Lee, Remy Lemoine, Sophie Le Pogam, Vincent Leveque, Jim Li, Joel McIntosh, Isabel Nájera, Jaehyeon Park, Aruna Railkar, Sonal Rajyaguru, Michael Sangi, Ryan C Schoenfeld, Leanna R Staben, Yunchou Tan, Joshua P Taygerly, Armando G Villaseñor, Paul E Weller.
Abstract
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.Entities:
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Year: 2013 PMID： 24195700 PMCID： PMC3954946 DOI： 10.1021/jm401329s
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446