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 5: Exploration of pyridazinones containing 6-amino-substituents.
abstract: The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
authors.affiliation: Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. pdragovich@anadyspharma.com
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Julie K
authors.initials: JK
authors.lastname: Blazel
authors.forename: David A
authors.initials: DA
authors.lastname: Ellis
authors.forename: Qing
authors.initials: Q
authors.lastname: Han
authors.forename: Ruhi
authors.initials: R
authors.lastname: Kamran
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kissinger
authors.forename: Laurie A
authors.initials: LA
authors.lastname: LeBrun
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Murphy
authors.forename: Michael
authors.initials: M
authors.lastname: Noble
authors.forename: Rupal A
authors.initials: RA
authors.lastname: Patel
authors.forename: Frank
authors.initials: F
authors.lastname: Ruebsam
authors.forename: Maria V
authors.initials: MV
authors.lastname: Sergeeva
authors.forename: Amit M
authors.initials: AM
authors.lastname: Shah
authors.forename: Richard E
authors.initials: RE
authors.lastname: Showalter
authors.forename: Chinh V
authors.initials: CV
authors.lastname: Tran
authors.forename: Mei
authors.initials: M
authors.lastname: Tsan
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Leo
authors.initials: L
authors.lastname: Kirkovsky
authors.forename: Yuefen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry; D015195:Drug Design; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003499:Cyclic S-Oxides; D012321:DNA-Directed RNA Polymerases; D011724:Pyridazines; D013829:Thiadiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase