title: Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease.
abstract: Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
authors.affiliation: Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. david.sperandio@celera.com
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Gangloff
authors.forename: Joane
authors.initials: J
authors.lastname: Litvak
authors.forename: Richard
authors.initials: R
authors.lastname: Goldsmith
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hataye
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Wang
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Shelton
authors.forename: Kyle
authors.initials: K
authors.lastname: Elrod
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: James M
authors.initials: JM
authors.lastname: Clark
authors.forename: Ken
authors.initials: K
authors.lastname: Rice
authors.forename: Steve
authors.initials: S
authors.lastname: Weinheimer
authors.forename: Kap-Sun
authors.initials: KS
authors.lastname: Yeung
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Dennis
authors.initials: D
authors.lastname: Hernandez
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Staab
authors.forename: Brian L
authors.initials: BL
authors.lastname: Venables
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Spencer
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D004492:Edetic Acid; D016174:Hepacivirus / Q000201:enzymology*; D007202:Indicators and Reagents; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D015032:Zinc / Q000494:pharmacology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D001562:Benzimidazoles; D004492:Edetic Acid; D007202:Indicators and Reagents; D010455:Peptides; D012367:RNA, Viral; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D015032:Zinc; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus