title: Synthesis and SAR of acyclic HCV NS3 protease inhibitors with novel P4-benzoxaborole moieties.
abstract: We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.
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: 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
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.forename: Richard M
authors.initials: RM
authors.lastname: Grimes
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: Zhi-Jie
authors.initials: ZJ
authors.lastname: Ni
authors.forename: Wuxin
authors.initials: W
authors.lastname: Zou
authors.forename: Jon
authors.initials: J
authors.lastname: Wright
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: 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