title: Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids.
abstract: Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
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: Junping
authors.initials: J
authors.lastname: Zhao
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: Al
authors.initials: A
authors.lastname: Lui
authors.forename: Beihan
authors.initials: B
authors.lastname: Wang
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 J P
authors.initials: VJ
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: Bill
authors.initials: B
authors.lastname: Fitch
authors.forename: Michael
authors.initials: M
authors.lastname: Brandl
authors.forename: Mohammad
authors.initials: M
authors.lastname: Masjedizadeh
authors.forename: Shao-Yong
authors.initials: SY
authors.lastname: Wu
authors.forename: Steve
authors.initials: S
authors.lastname: de Keczer
authors.forename: Tatyana
authors.initials: T
authors.lastname: Voronin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011760:Pyrrolidinones; D013843:Thiazines; D017361:Viral Nonstructural Proteins; C009435:tetramic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase