N-(4-Amino-1-cyclobutyl-3,4-dioxobutan-2-yl)-3-{N-[(tert-butylamino)(hydroxy)methylidene]-3-methylvalyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboximidic acid

BeschreibungIn May 2011, the U.S. FDA approved boceprevir (SCH-503034), to be given in combination with peginterferon alfa plus ribavirin, for the treatment of patients with chronic hepatitis C genotype 1 viral infection. Boceprevir and telaprevir are the first hepatitis C virus (HCV) protease inhibitors to be approved for the treatment of HCV infection. Boceprevir is an inhibitor of HCV NS3-4A protease, an essential enzyme required by HCV for posttranslational processing of viral proteins into their mature forms. Boceprevir binds covalently, but reversibly, to the active site serine by addition of the hydroxyl group to the keto-amide functionality. Boceprevir inhibits HCV NS3-4A protease with a Ki of 14 nM. In cell culture, the EC50 of boceprevir was 200 nM for an HCV replicon constructed from genotype 1b. Boceprevir was two-to threefold less potent against HCV replicon from genotypes 1a, 2, and 3. The potency of boceprevir decreased threefold in the presence of human serum. Boceprevir was discovered through a series of systematic truncations and modifications of a keto-amide undecapeptide lead molecule. Boceprevir is synthesized by coupling of 3-amino-4- cyclobutyl-2-hydroxybutyramide or the related oxobutyramide with a cyclopropyl-pyrrolidine carboxylic acid intermediate. The pyrrolidine derivative can be prepared via cyclopropanation of a bicyclic lactam derivative or by conversion of 3,3-dimethylcyclopropane-1,2-dicarboxylic acid to the pyrrolidine in a multistep route. Boceprevir is a 1:1 mixture of diastereomers at the readily epimerizable position a to the keto group.

VerwendenAn NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. It is a COVID19-related research product.