Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates.
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.
Li
Xianfeng
X
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Zhang
Yong-Kang
YK
Liu
Yang
Y
Ding
Charles Z
CZ
Zhou
Yasheen
Y
Li
Qun
Q
Plattner
Jacob J
JJ
Baker
Stephen J
SJ
Zhang
Suoming
S
Kazmierski
Wieslaw M
WM
Wright
Lois L
LL
Smith
Gary K
GK
Grimes
Richard M
RM
Crosby
Renae M
RM
Creech
Katrina L
KL
Carballo
Luz H
LH
Slater
Martin J
MJ
Jarvest
Richard L
RL
Thommes
Pia
P
Hubbard
Julia A
JA
Convery
Maire A
MA
Nassau
Pamela M
PM
McDowell
William
W
Skarzynski
Tadeusz J
TJ
Qian
Xuelei
X
Fan
Dazhong
D
Liao
Liang
L
Ni
Zhi-Jie
ZJ
Pennicott
Lewis E
LE
Zou
Wuxin
W
Wright
Jon
J
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
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