Inhibitors of HCV NS5B polymerase. Part 2: Evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid.
ABSTRACT A novel series of non-nucleoside HCV NS5B polymerase inhibitors was prepared from a (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid template. Solution and solid phase analog synthesis focused on the northern region of the template combined with structure based design led to the discovery of several potent and orally bioavailable lead compounds.
Chapter: Viral RNA Polymerase Inhibitors[Show abstract] [Hide abstract]
ABSTRACT: Infections by RNA viruses continue to exist as significant public health problems worldwide. In response to the urgent need for safer and more efficacious treatment options against infections caused by RNA viruses, the pharmaceutical and biotechnology industries have devoted significant efforts over the last two decades to discovering and developing new antiviral agents. As the primary viral enzyme responsible for genome replication and transcription, RNA-dependent RNA polymerases (RdRps) emerged early and remained as one of the most promising targets for therapeutic intervention of RNA virus infections. Advances in both basic research and drug discovery technology have resulted in the identification of a significant number of nucleoside (NIs) and non-nucleoside inhibitors (NNIs) of viral RdRps. In this chapter, we will focus our attention on various classes of viral RdRp inhibitors, with main emphases on those of hepatitis C virus (HCV) due to its significant unmet medical need. Recent progress in understanding their mechanism of action, antiviral activity profiles, and emergence of drug resistance mutations will be discussed.12/2008: pages 527-548;
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ABSTRACT: Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.(1) In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.Medicinal Research Reviews 09/2013; 33(5):934-984. · 9.58 Impact Factor
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ABSTRACT: Using a support vector machine (SVM), three classification models were built to predict whether a compound is an active or weakly active inhibitor based on a dataset of 386 hepatitis C virus (HCV) NS5B polymerase NNIs (non-nucleoside analogue inhibitors) fitting into the pocket of the NNI III binding site. For each molecule, global descriptors, 2D and 3D property autocorrelation descriptors were calculated from the program ADRIANA.Code. Three models were developed with the combination of different types of descriptors. Model 2 based on 16 global and 2D autocorrelation descriptors gave the highest prediction accuracy of 88.24% and MCC (Matthews correlation coefficient) of 0.789 on test set. Model 1 based on 13 global descriptors showed the highest prediction accuracy of 86.25% and MCC of 0.732 on external test set (including 80 compounds). Some molecular properties such as molecular shape descriptors (InertiaZ, InertiaX and Span), number of rotatable bonds (NRotBond), water solubility (LogS), and hydrogen bonding related descriptors performed important roles in the interactions between the ligand and NS5B polymerase.International Journal of Molecular Sciences 01/2012; 13(4):4033-47. · 2.46 Impact Factor