Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups.

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Tytuł:: Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups.
Autorzy:: Venkatraman S; Schering Plough Research Institute, K15-MS 3545, 2015, Galloping Hill Road, Kenilworth, NJ 07033, United States. />Velazquez F
Wu W
Blackman M
Madison V
Njoroge FG
Źródło:: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Apr 01; Vol. 20 (7), pp. 2151-5. Date of Electronic Publication: 2010 Feb 14.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
MeSH Terms:: Amides/*pharmacology
Antiviral Agents/*pharmacology
Hepacivirus/*enzymology
Hepatitis C/*drug therapy
Viral Nonstructural Proteins/*antagonists & inhibitors
Viral Nonstructural Proteins/*metabolism
Amides/chemistry ; Antiviral Agents/chemistry ; Humans ; Proline/analogs & derivatives ; Proline/pharmacology ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Structure-Activity Relationship
Substance Nomenclature:: 0 (Amides)
0 (Antiviral Agents)
0 (NS3 protein, hepatitis C virus)
0 (Protease Inhibitors)
0 (Viral Nonstructural Proteins)
89BT58KELH (N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide)
9DLQ4CIU6V (Proline)
Entry Date(s):: Date Created: 20100316 Date Completed: 20100705 Latest Revision: 20141120
Update Code:: 20240104
DOI:: 10.1016/j.bmcl.2010.02.051
PMID:: 20226659
: Czasopismo naukowe

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Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P(1) had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P(1) group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir.
(2010 Elsevier Ltd. All rights reserved.)

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