Discovery of N-[4-[6-tert-Butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]phenyl]methanesulfonamide (RG7109), a Potent Inhibitor of the Hepatitis C Virus NS5B Polymerase

Citations Over TimeTop 21% of 2013 papers

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.

Related Papers

• → Synthesis of pyrrolidine analogues of solamin(2005)10 cited
• → ChemInform Abstract: OPTICAL ACTIVATION OF 2‐PHENYLPROPIONALDEHYDE VIA SOME 2‐SUBSTITUTED PYRROLIDINE ENAMINES(1978)
• Synthesis of Mercaptoalkoxy quinoline Compounds(2002)
• → Synthesis of benzo[g]quinoline derivatives(1970)
• → Carcinogenic Activity of Analogues of <italic>p</italic>-Dimethylaminoazobenzene. IV. Activity of the Quinoline Analogues<xref ref-type="fn" rid="FN1">2</xref>(1961)