title: Discovery of novel urea-based hepatitis C protease inhibitors with high potency against protease-inhibitor-resistant mutants.
abstract: The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
authors.affiliation: GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. wieslaw.m.kazmierski@gsk.com
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
authors.forename: Gary K
authors.initials: GK
authors.lastname: Smith
authors.forename: Richard L
authors.initials: RL
authors.lastname: Jarvest
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Ji
authors.forename: Joel P
authors.initials: JP
authors.lastname: Cooper
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Tallant
authors.forename: Renae M
authors.initials: RM
authors.lastname: Crosby
authors.forename: Katrina
authors.initials: K
authors.lastname: Creech
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.forename: Suoming
authors.initials: S
authors.lastname: Zhang
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Ding
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Wei
authors.initials: W
authors.lastname: Bu
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D057927:Hydrophobic and Hydrophilic Interactions; D008099:Liver / Q000378:metabolism; D009154:Mutation; D051381:Rats; D012093:Replicon / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D015842:Serine Proteinase Inhibitors; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases