title: Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.
abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
authors.affiliation: Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Yuefen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Murphy
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Stankovic
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertolini
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Sun
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ayida
authors.forename: Chinh V
authors.initials: CV
authors.lastname: Tran
authors.forename: Frank
authors.initials: F
authors.lastname: Ruebsam
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Amit M
authors.initials: AM
authors.lastname: Shah
authors.forename: Mei
authors.initials: M
authors.lastname: Tsan
authors.forename: Richard E
authors.initials: RE
authors.lastname: Showalter
authors.forename: Rupal
authors.initials: R
authors.lastname: Patel
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Lebrun
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: Ruhi
authors.initials: R
authors.lastname: Kamran
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brooks
authors.forename: Maria V
authors.initials: MV
authors.lastname: Sergeeva
authors.forename: Leo
authors.initials: L
authors.lastname: Kirkovsky
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kissinger
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D011724:Pyridazines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase