Synthesis and evaluation of novel alpha-amino cyclic boronates as inhibitors of HCV NS3 protease.
We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.
Li
Xianfeng
X
Anacor Pharmaceuticals, Inc., Palo Alto, CA 94303, USA. xli@anacor.com
Zhang
Yong-Kang
YK
Liu
Yang
Y
Ding
Charles Z
CZ
Li
Qun
Q
Zhou
Yasheen
Y
Plattner
Jacob J
JJ
Baker
Stephen J
SJ
Qian
Xuelei
X
Fan
Dazhong
D
Liao
Liang
L
Ni
Zhi-Jie
ZJ
White
Gemma V
GV
Mordaunt
Jackie E
JE
Lazarides
Linos X
LX
Slater
Martin J
MJ
Jarvest
Richard L
RL
Thommes
Pia
P
Ellis
Malcolm
M
Edge
Colin M
CM
Hubbard
Julia A
JA
Somers
Don
D
Rowland
Paul
P
Nassau
Pamela
P
McDowell
Bill
B
Skarzynski
Tadeusz J
TJ
Kazmierski
Wieslaw M
WM
Grimes
Richard M
RM
Wright
Lois L
LL
Smith
Gary K
GK
Zou
Wuxin
W
Wright
Jon
J
Pennicott
Lewis E
LE
D001897:Boronic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D020134:Catalytic Domain; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D015394:Molecular Structure; D012694:Serine / Q000737:chemistry; 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
D001897:Boronic Acids; D012694:Serine; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases