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.
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.
authors.affiliation: Department of Medicinal Chemistry and Drug Metabolism, the Musculoskeletal, Microbial and Proliferative Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426, USA. Rosanna_2_Tedesco@gsk.com
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tedesco
authors.forename: Antony N
authors.initials: AN
authors.lastname: Shaw
authors.forename: Ramesh
authors.initials: R
authors.lastname: Bambal
authors.forename: Deping
authors.initials: D
authors.lastname: Chai
authors.forename: Nestor O
authors.initials: NO
authors.lastname: Concha
authors.forename: Michael G
authors.initials: MG
authors.lastname: Darcy
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.forename: Duke M
authors.initials: DM
authors.lastname: Fitch
authors.forename: Adam
authors.initials: A
authors.lastname: Gates
authors.forename: Warren G
authors.initials: WG
authors.lastname: Gerhardt
authors.forename: Dina L
authors.initials: DL
authors.lastname: Halegoua
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Hofmann
authors.forename: Victor K
authors.initials: VK
authors.lastname: Johnston
authors.forename: Arun C
authors.initials: AC
authors.lastname: Kaura
authors.forename: Nannan
authors.initials: N
authors.lastname: Liu
authors.forename: Richard M
authors.initials: RM
authors.lastname: Keenan
authors.forename: Juili
authors.initials: J
authors.lastname: Lin-Goerke
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sarisky
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wiggall
authors.forename: Michael N
authors.initials: MN
authors.lastname: Zimmerman
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Duffy
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C508992:1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone; D000998:Antiviral Agents; D001581:Benzothiadiazines; D001798:Blood Proteins; D015363:Quinolones; D013829:Thiadiazines; D012324:RNA-Dependent RNA Polymerase