title: Discovery of novel P3-oxo inhibitor of hepatitis C virus NS3/4A serine protease.
abstract: A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
authors.affiliation: Infectious Disease CEDD, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. duanmaosheng@hdbiosciences.com
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Kazmierski
authors.forename: Renae
authors.initials: R
authors.lastname: Crosby
authors.forename: Margaret
authors.initials: M
authors.lastname: Gartland
authors.forename: Jinjing
authors.initials: J
authors.lastname: Ji
authors.forename: Matt
authors.initials: M
authors.lastname: Tallant
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Lois
authors.initials: L
authors.lastname: Wright
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Ding
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Suoming
authors.initials: S
authors.lastname: Zhang
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
mesh_terms: D003521:Cyclopropanes; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D054833:Isoindoles; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D015394:Molecular Structure; D009154:Mutation; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011392:Proline; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir