| InChI | InChI=1S/C26H37NO4S.K/c1-17-8-10-19(11-9-17)25(28)27(20-12-14-21(31-2)15-13-20)22-16-23(32-24(22)26(29)30)18-6-4-3-5-7-18;/h6,16-17,19-21H,3-5,7-15H2,1-2H3,(H,29,30);/q;+1/p-1 |
| Reference | <p style=/line-height:25px/>
<br>[1]. Ludmila Gerber, Tania M. Welzel, Stefan Zeuzem. New therapeutic strategies in HCV: polymerase inhibitors. Liver International. 2013,33(s1): 85-92
Abstract
The characterization of the viral life cycle facilitated the development of directly acting antiviral drugs. Among those, several inhibitors of the viral RNA-dependent RNA polymerase have proven effectiveness in clinical trials. The characteristics of different nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as their clinical applications and combinations with other classes of directly acting antiviral drugs are reviewed herein.
<br>[2]. Abdelrahman S. Mayhoub. Hepatitis C RNA-dependent RNA polymerase inhibitors: A review of structure-activity and resistance relationships; different scaffolds and mutations. Bioorganic & Medicinal Chemistry. 2012, 20 (10): 3150-3161.
Abstract
Hepatitis C virus (HCV), like many other flaviviruses, is widely distributed worldwide with estimated chronically infected victims between 170 and 200 million. HCV inherent error-prone RNA-dependent RNA polymerase (RdRp) is an attractive target for medicinal chemists because of the conservative nature of NS5B nucleotide-binding site. In addition, the availability of several crystal structures for HCV RdRp paved the road for conducting rational-based drug design. At the same time, RdRp is responsible for high mutation rate and rapid development of resistance to the clinically-used therapeutics. To improve the viral response, combination therapy is regularly used. The success of co-therapy disciplines depends on targeting two different active sites. This review provides an overview about different scaffolds that target HCV RdPp with insights about their binding modes and possible induced mutant strains.
<br>[3]. Debasis Dasa, Jian Honga, Shu-Hui Chena, et al. Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors. Bioorganic & Medicinal Chemistry. 2011, 19(16): 4690-4703
Abstract
Hepatitis C virus (HCV) is a major health burden, with an estimated 170 million chronically infected individuals worldwide, and a leading cause of liver transplantation. Patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. In the past two decades, several approaches have been adopted to inhibit non-structural viral proteins. The RNA-dependent RNA polymerase (NS5B) of HCV is one of the attractive validated targets for development of new drugs to block HCV infection. In this review, we report the recent progress made towards identifying and developing benzothiadiazines as HCV NS5B polymerase inhibitors. The substituted benzothiadiazine class was identified by HTS in 2002 as an NS5B inhibitor. Further optimization and modification of the core has improved the potency and pharmacokinetic properties of substituted benzothiadiazines. Research on palm site-binding benzothiadiazine analogs and related derivatives and analogs is discussed in this article.
<br>[4]. Pierre L Beaulieu. Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection. Informahealthcare. 2009, 19(2): 145-164
Abstract
Background: 170 to 200 million people worldwide are believed to suffer from chronic hepatitis C virus (HCV) infection, a blood-born disease that targets the liver and progresses to organ cirrhosis and primary cancer in a significant proportion of patients. The currently available treatment has limited efficacy and suffers from restricting side effects. HCV infection is the principal cause of liver transplant in industrialized nations and between 8000 and 10,000 deaths result annually from the disease in the United States alone. Virus-specific, more efficacious, and better-tolerated anti-HCV therapies are thus required to address the unmet medical need. Objective: To review progress achieved since 2005 in the development of HCV NS5B polymerase inhibitors as potential therapy for the treatment of HCV infection with a primary focus on available patent and medical literature. Results/conclusion: Several classes of small-molecule inhibitors of HCV NS5B have progressed into clinical development and demonstrated efficacy in reducing viral load in infected patients. The results so far provide an encouraging foundation for the development of novel, more tolerable therapies and addressing emergence of resistance through combination of antiviral agents with complementary mechanisms of action.
<br>[5]. Safety,Tolerability and Pharmacokinetics of Multiple Ascending Doses of VCH 916 in Subjects With Chronic Hep C Infection
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