Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease.
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
Sperandio
David
D
Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. david.sperandio@celera.com
Gangloff
Anthony R
AR
Litvak
Joane
J
Goldsmith
Richard
R
Hataye
Jason M
JM
Wang
Vivian R
VR
Shelton
Emma J
EJ
Elrod
Kyle
K
Janc
James W
JW
Clark
James M
JM
Rice
Ken
K
Weinheimer
Steve
S
Yeung
Kap-Sun
KS
Meanwell
Nicholas A
NA
Hernandez
Dennis
D
Staab
Andrew J
AJ
Venables
Brian L
BL
Spencer
Jeffrey R
JR
D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D004492:Edetic Acid; D016174:Hepacivirus / Q000201:enzymology*; D007202:Indicators and Reagents; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D015032:Zinc / Q000494:pharmacology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D001562:Benzimidazoles; D004492:Edetic Acid; D007202:Indicators and Reagents; D010455:Peptides; D012367:RNA, Viral; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D015032:Zinc; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus