Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease.
We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303, USA. charles.ding@gmail.com
Charles Z
CZ
Ding
Yong-Kang
YK
Zhang
Xianfeng
X
Li
Yang
Y
Liu
Suoming
S
Zhang
Yasheen
Y
Zhou
Jacob J
JJ
Plattner
Stephen J
SJ
Baker
Liang
L
Liu
Maosheng
M
Duan
Richard L
RL
Jarvest
Jingjing
J
Ji
Wieslaw M
WM
Kazmierski
Matthew D
MD
Tallant
Lois L
LL
Wright
Gary K
GK
Smith
Renae M
RM
Crosby
Amy A
AA
Wang
Zhi-Jie
ZJ
Ni
Wuxin
W
Zou
Jon
J
Wright
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D016174:Hepacivirus / Q000201:enzymology*; D007546:Isoquinolines / Q000737:chemistry; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / 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
D000998:Antiviral Agents; D007546:Isoquinolines; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C039109:isoquinoline