title: Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure-activity relationships of benzothiazine-substituted quinolinediones.
abstract: A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
authors.affiliation: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. javier.devicente@roche.com
authors.forename: Javier
authors.initials: J
authors.lastname: de Vicente
authors.forename: Robert T
authors.initials: RT
authors.lastname: Hendricks
authors.forename: David B
authors.initials: DB
authors.lastname: Smith
authors.forename: Jay B
authors.initials: JB
authors.lastname: Fell
authors.forename: John
authors.initials: J
authors.lastname: Fischer
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Spencer
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stengel
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: John E
authors.initials: JE
authors.lastname: Robinson
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Ramona K
authors.initials: RK
authors.lastname: Hilgenkamp
authors.forename: Calvin
authors.initials: C
authors.lastname: Yee
authors.forename: George
authors.initials: G
authors.lastname: Adjabeng
authors.forename: Todd R
authors.initials: TR
authors.lastname: Elworthy
authors.forename: Jahari
authors.initials: J
authors.lastname: Tracy
authors.forename: Elbert
authors.initials: E
authors.lastname: Chin
authors.forename: Jim
authors.initials: J
authors.lastname: Li
authors.forename: Beihan
authors.initials: B
authors.lastname: Wang
authors.forename: Joe T
authors.initials: JT
authors.lastname: Bamberg
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stephenson
authors.forename: Connie
authors.initials: C
authors.lastname: Oshiro
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Manjiri
authors.initials: M
authors.lastname: Ghate
authors.forename: Vincent
authors.initials: V
authors.lastname: Leveque
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Sonal
authors.initials: S
authors.lastname: Rajyaguru
authors.forename: Gloria
authors.initials: G
authors.lastname: Ao-Ieong
authors.forename: Ludmila
authors.initials: L
authors.lastname: Alexandrova
authors.forename: Susan
authors.initials: S
authors.lastname: Larrabee
authors.forename: Michael
authors.initials: M
authors.lastname: Brandl
authors.forename: Andrew
authors.initials: A
authors.lastname: Briggs
authors.forename: Sunil
authors.initials: S
authors.lastname: Sukhtankar
authors.forename: Robert
authors.initials: R
authors.lastname: Farrell
authors.forename: Brian
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases; D004791:Enzyme Inhibitors; D011804:Quinolines; D015363:Quinolones; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase