Structure-activity relationship studies of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of HCV NS3 serine protease.
A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. However, Zn(2+)-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the presence of negatively charged functionality. This result was interpreted in the context of an initial electrostatic interaction between protease and inhibitor that is subsequently consolidated by Zn(2+), with binding facilitated by the featureless active site and proximal regions of the HCV NS3 protein.
Yeung
K S
KS
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, POBox 5100, Wallingford, CT 06492, USA. kapsun.yeung@bms.com
Meanwell
N A
NA
Qiu
Z
Z
Hernandez
D
D
Zhang
S
S
McPhee
F
F
Weinheimer
S
S
Clark
J M
JM
Janc
J W
JW
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001671:Biochemistry / Q000379:methods; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015032:Zinc / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D001562:Benzimidazoles; D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D015032:Zinc; C442390:APC 6336; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases