Exploration of acyl sulfonamides as carboxylic acid replacements in protease inhibitors of the hepatitis C virus full-length NS3.
The hepatitis C virus (HCV) NS3 protease has emerged as a promising anti-HCV drug target. Herein, we present an investigation of NS3 inhibitors comprising the acyl sulfonamide functionality. A series of tetra- and tripeptide based acyl sulfonamide inhibitors and their structure-activity relationships from both enzymatic and cell-based in vitro assays are presented. In summary, the acidity of the acyl sulfonamide functionality, the character of the P1 side chain, and the acyl sulfonamide substituent were found to be important for the inhibitory potencies.
Rönn
Robert
R
Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Sabnis
Yogesh A
YA
Gossas
Thomas
T
Akerblom
Eva
E
Danielson
U Helena
UH
Hallberg
Anders
A
Johansson
Anja
A
D000595:Amino Acid Sequence; D002264:Carboxylic Acids / Q000737:chemistry*; D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000737:chemistry*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002264:Carboxylic Acids; D011480:Protease Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases