Investigation of glycine alpha-ketoamide HCV NS3 protease inhibitors: effect of carboxylic acid isosteres

Wei Han; Xiangjun Jiang; Zilun Hu; Zelda R Wasserman; Carl P Decicco

doi:10.1016/j.bmcl.2005.06.003

Investigation of glycine alpha-ketoamide HCV NS3 protease inhibitors: effect of carboxylic acid isosteres

Bioorg Med Chem Lett. 2005 Aug 1;15(15):3487-90. doi: 10.1016/j.bmcl.2005.06.003.

Authors

Wei Han¹, Xiangjun Jiang, Zilun Hu, Zelda R Wasserman, Carl P Decicco

Affiliation

¹ Discovery Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, USA. [email protected]

PMID: 15982872
DOI: 10.1016/j.bmcl.2005.06.003

Abstract

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.

MeSH terms

Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology
Binding Sites
Carboxylic Acids / chemistry
Glycine / analogs & derivatives*
Glycine / chemical synthesis
Glycine / pharmacology
Hepacivirus / enzymology*
Inhibitory Concentration 50
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Structure-Activity Relationship
Sulfonic Acids / chemistry
Tetrazoles / chemistry
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Amides
Carboxylic Acids
NS3 protein, hepatitis C virus
Protease Inhibitors
Sulfonic Acids
Tetrazoles
Viral Nonstructural Proteins
glycine alpha-ketoamide
1H-tetrazole
Glycine