4MIB

Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)

Summary for 4MIB

• Entry DOI: 10.2210/pdb4mib/pdb
• Related: 4MIA 4MK7 4MK8 4MK9 4MKA 4MKB
• Descriptor: RNA-DIRECTED RNA POLYMERASE, DIMETHYL SULFOXIDE, N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide, ... (4 entities in total)
• Functional Keywords: polymerase, transferase, ns5b, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26663
• Total number of polymer chains: 2
• Total formula weight: 127756.79

Authors

Harris, S.F.,Villasenor, A.G. (deposition date: 2013-08-30, release date: 2014-05-07, Last modification date: 2024-02-28)

Primary citation

Talamas, F.X.,Abbot, S.C.,Anand, S.,Brameld, K.A.,Carter, D.S.,Chen, J.,Davis, D.,de Vicente, J.,Fung, A.D.,Gong, L.,Harris, S.F.,Inbar, P.,Labadie, S.S.,Lee, E.K.,Lemoine, R.,Le Pogam, S.,Leveque, V.,Li, J.,McIntosh, J.,Najera, I.,Park, J.,Railkar, A.,Rajyaguru, S.,Sangi, M.,Schoenfeld, R.C.,Staben, L.R.,Tan, Y.,Taygerly, J.P.,Villasenor, A.G.,Weller, P.E.
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.
J.Med.Chem., 57:1914-1931, 2014

PubMed 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.

PubMed: 24195700
DOI: 10.1021/jm401329s

Experimental method

X-RAY DIFFRACTION (2.3 Å)