title: 4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase.
abstract: 4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).
authors.affiliation: Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ellis
authors.forename: Julie K
authors.initials: JK
authors.lastname: Blazel
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Chinh V
authors.initials: CV
authors.lastname: Tran
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Sun
authors.forename: Frank
authors.initials: F
authors.lastname: Ruebsam
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGuire
authors.forename: Alan X
authors.initials: AX
authors.lastname: Xiang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Yuefen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Qing
authors.initials: Q
authors.lastname: Han
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kissinger
authors.forename: Richard E
authors.initials: RE
authors.lastname: Showalter
authors.forename: Matthew
authors.initials: M
authors.lastname: Lardy
authors.forename: Amit M
authors.initials: AM
authors.lastname: Shah
authors.forename: Mei
authors.initials: M
authors.lastname: Tsan
authors.forename: Rupal
authors.initials: R
authors.lastname: Patel
authors.forename: Laurie A
authors.initials: LA
authors.lastname: LeBrun
authors.forename: Ruhi
authors.initials: R
authors.lastname: Kamran
authors.forename: Darian M
authors.initials: DM
authors.lastname: Bartkowski
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Nolan
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Norris
authors.forename: Maria V
authors.initials: MV
authors.lastname: Sergeeva
authors.forename: Leo
authors.initials: L
authors.lastname: Kirkovsky
mesh_terms: D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000201:enzymology*; D008956:Models, Chemical; D008968:Molecular Conformation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D011724:Pyridazines; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase