title: Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.
abstract: A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Li
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: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Suoming
authors.initials: S
authors.lastname: Zhang
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
authors.forename: Gary K
authors.initials: GK
authors.lastname: Smith
authors.forename: Richard M
authors.initials: RM
authors.lastname: Grimes
authors.forename: Renae M
authors.initials: RM
authors.lastname: Crosby
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Creech
authors.forename: Luz H
authors.initials: LH
authors.lastname: Carballo
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Slater
authors.forename: Richard L
authors.initials: RL
authors.lastname: Jarvest
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.forename: Julia A
authors.initials: JA
authors.lastname: Hubbard
authors.forename: Maire A
authors.initials: MA
authors.lastname: Convery
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Nassau
authors.forename: William
authors.initials: W
authors.lastname: McDowell
authors.forename: Tadeusz J
authors.initials: TJ
authors.lastname: Skarzynski
authors.forename: Xuelei
authors.initials: X
authors.lastname: Qian
authors.forename: Dazhong
authors.initials: D
authors.lastname: Fan
authors.forename: Liang
authors.initials: L
authors.lastname: Liao
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Ni
authors.forename: Lewis E
authors.initials: LE
authors.lastname: Pennicott
authors.forename: Wuxin
authors.initials: W
authors.lastname: Zou
authors.forename: Jon
authors.initials: J
authors.lastname: Wright
mesh_terms: D001665:Binding Sites; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000187:drug effects; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; 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: D001896:Boron Compounds; D001897:Boronic Acids; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases