Synthesis of new acylsulfamoyl benzoxaboroles as potent inhibitors of HCV NS3 protease.
HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA. xli@anacor.com
Xianfeng
X
Li
Yong-Kang
YK
Zhang
Yang
Y
Liu
Suoming
S
Zhang
Charles Z
CZ
Ding
Yasheen
Y
Zhou
Jacob J
JJ
Plattner
Stephen J
SJ
Baker
Liang
L
Liu
Wei
W
Bu
Wieslaw M
WM
Kazmierski
Lois L
LL
Wright
Gary K
GK
Smith
Richard L
RL
Jarvest
Maosheng
M
Duan
Jing-Jing
JJ
Ji
Joel P
JP
Cooper
Matthew D
MD
Tallant
Renae M
RM
Crosby
Katrina
K
Creech
Zhi-Jie
ZJ
Ni
Wuxin
W
Zou
Jon
J
Wright
D000818:Animals; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020134:Catalytic Domain; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D001896:Boron 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