1217428-98-2Relevant articles and documents
1H-imidazole-2,5-dicarboxamides as ns4a peptidomimetics: Identification of a new approach to inhibit hcv-ns3 protease
Arold, Stefan T.,Asfour, Hani Z.,Bamane, Faida H.,El-Araby, Moustafa E.,Elfaky, Mahmoud A.,Khayat, Maan T.,Omar, Abdelsattar M.,Soror, Sameh H.
, (2020)
The nonstructural (NS) protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been considered in the literature and, therefore, we decided to explore this strategy for developing a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25‘ to Arg-28‘ at the core of NS4A21‘–33‘ needed to activate the NS3 protease. Some of the synthesized compounds (Coded MOC) were able to compete with and displace NS4A21‘–33‘ for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21‘–33‘ with a competition half maximal inhibitory concentration (IC50) of 1.9 ± 0.12 μM in a fluorescence anisotropy assay and stabilized the denaturation of NS3 by increasing the aggregation temperature (40% compared to NS4A21‘–33‘). MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations were conducted to rationalize the differences in structure–activity relationship (SAR) between the active MOC-24 and the inactive MOC-26. Our data show that MOC compounds are possibly the first examples of NS4A peptidomimetics that have demonstrated promising activities against NS3 proteins.
IMIDAZOLE-BASED COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS
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Paragraph 0143, (2020/11/30)
Imidazole-based compounds as hepatitis C virus (HCV) inhibitors. The compounds have an imidazole core that is disubstituted via amide links. Also described are a pharmaceutical composition incorporating the imidazole-based compound, a method of preparing these compounds, and a method for using the pharmaceutical composition in the treatment of HCV infection.
PYRAZOLO[3,4-b]PYRIDINE AND PYRROLO[2,3-b]PYRIDINE INHIBITORS OF BRUTON'S TYROSINE KINASE
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Paragraph 0808, (2018/07/31)
Disclosed are pyrazolo[3,4-b]pyridine and pyrrolo[2,3-b]pyridine inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, alone or in combin
