Investigation of glycine alpha-ketoamide HCV NS3 protease inhibitors: effect of carboxylic acid isosteres.
The design and synthesis of tetrapeptide-based alpha-ketoamides containing prime side acid isosteres HCV NS3 protease inhibitors are described. Tetrazole, sulfonic acid, and N-sulfonylcarboxamids were demonstrated to be efficient carboxylic acid replacements. Further optimization yielded a series of potent HCV NS3 protease inhibitors with IC(50) of 0.020-0.060 microM.
Han
Wei
W
Discovery Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, USA. wei.han1@bms.com
Jiang
Xiangjun
X
Hu
Zilun
Z
Wasserman
Zelda R
ZR
Decicco
Carl P
CP
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry; D013777:Tetrazoles / Q000737:chemistry; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D002264:Carboxylic Acids; D005998:Glycine; D011480:Protease Inhibitors; D013451:Sulfonic Acids; D013777:Tetrazoles; 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; C045574:1H-tetrazole