title: Potent inhibitors of HCV-NS3 protease derived from boronic acids.
abstract: Chronic hepatitis C infection is the leading causes for cirrhosis of the liver and hepatocellular carcinoma, leading to liver failure and liver transplantation. The etiological agent, HCV virus produces a single positive strand of RNA that is processed with the help of serine protease NS3 to produce mature virus. Inhibition of NS3 protease can be potentially used to develop effective drugs for HCV infections. Numerous efforts are now underway to develop potent inhibitors of HCV protease that contain ketoamides as serine traps. Herein we report the synthesis of a series of potent inhibitors that contain a boronic acid as a serine trap. The activity of these compounds were optimized to 200pM. X-ray structure of compound 17 bound to NS3 protease is also discussed.
authors.affiliation: Schering Plough Research Institute, K15-MS 3545, Kenilworth, NJ 07033, USA. Srikanth.Venkatraman@spcorp.com
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Wanli
authors.initials: W
authors.lastname: Wu
authors.forename: Andrew
authors.initials: A
authors.lastname: Prongay
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: F
authors.initials: F
authors.lastname: George Njoroge
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000577:Amides; D000998:Antiviral Agents; D001897:Boronic Acids; 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