title: Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups.
abstract: We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA. xli@anacor.com
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
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
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Ding
authors.forename: Suoming
authors.initials: S
authors.lastname: Zhang
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
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D006146:Guanidines / Q000737:chemistry; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010072:Oxamic Acid / Q000737:chemistry; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000577:Amides; D000998:Antiviral Agents; D002219:Carbamates; D006146:Guanidines; D010072:Oxamic Acid; 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; C004711:dicyandiamido