Glycine alpha-ketoamides as HCV NS3 protease inhibitors.
Using a tetrapeptide-based alpha-ketoamide template, various amines and amino acids were incorporated to explore the prime side of the HCV NS3 protease catalytic site. Glycine carboxylic acid was found to be the most effective prime group. Further optimization yielded an inhibitor with IC(50) of 0.060 microM.
Han
Wei
W
Department of Discovery Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA. wei.han1@bms.com
Hu
Zilun
Z
Jiang
Xiangjun
X
Wasserman
Zelda R
ZR
Decicco
Carl P
CP
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000588:Amines / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D005998:Glycine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D011480:Protease Inhibitors / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D000588:Amines; D000596:Amino Acids; D005998:Glycine; 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; C478046:glycine alpha-ketoamide