PDBsum entry 2fvc

Transferase

PDB id: 2fvc

Contents

Protein chains

563 a.a.

Ligands

888 ×2

Waters ×641

References listed in PDB file

Key reference

• Title: 3-(1,1-Dioxo-2h-(1,2,4)-Benzothiadiazin-3-Yl)-4-Hydroxy-2(1h)-Quinolinones, Potent inhibitors of hepatitis c virus RNA-Dependent RNA polymerase.
• Authors: R.Tedesco, A.N.Shaw, R.Bambal, D.Chai, N.O.Concha, M.G.Darcy, D.Dhanak, D.M.Fitch, A.Gates, W.G.Gerhardt, D.L.Halegoua, C.Han, G.A.Hofmann, V.K.Johnston, A.C.Kaura, N.Liu, R.M.Keenan, J.Lin-Goerke, R.T.Sarisky, K.J.Wiggall, M.N.Zimmerman, K.J.Duffy.
• Ref.: J Med Chem, 2006, 49, 971-983. [DOI no: 10.1021/jm050855s]
• PubMed id: 16451063

Abstract

Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.