title: Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides.
abstract: A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
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: 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: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: April
authors.initials: A
authors.lastname: Wong
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: 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
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase