Emerging therapies for hepatitis C virus.
ABSTRACT Currently, 170 million people worldwide are affected by the HCV. Chronic HCV infection is amongst the leading causes of chronic liver disease and its complications such as cirrhosis and hepatocellular carcinoma, making it the most common reason for liver transplantation. The current standard of treatment for HCV is pegylated IFN-α plus ribavirin. This treatment, when administered for the standard duration, allows sustained virological response (SVR) in ∼ 50% of patients infected with HCV and about 40% for HCV genotype 1, the most prevalent form of HCV in the US. SVR rates for populations with co-morbidities (patients with chronic renal disease) and certain ethnic backgrounds (African Americans and Hispanics) are lower. Given the high prevalence and relatively low cure rates of current antiviral therapy, the burden of HCV is enormous.
Faced with this urgent and growing medical need, research into novel therapeutic compounds for the treatment of HCV is a rapidly growing industry. Several novel compounds are in advanced stages of clinical development, such as HCV protease inhibitors (particularly those against NS3-4A protease), HCV polymerase inhibitors (including both nucleoside and non-nucleoside analogs) and cyclophilin inhibitors.
HCV treatment has seen many advances in the last decade and the discovery process has been fraught with both successes and disappointments. Through a process of rigorous research, the current late stage novel HCV therapeutics seem to have overcome some of the obstacles met by their early predecessors and offer the promise of meeting the shortfalls of the current standard of treatment.
Data from clinical trials are encouraging and suggest that combination therapies of these novel agents may have the potential to shorten treatment duration and increase viral clearance when used in conjunction with pegylated IFN-α and ribavirin.
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ABSTRACT: The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50=0.003μM), highly selective, and safe in in vitro and in vivo assays.Bioorganic & medicinal chemistry letters 11/2013; 23(24). DOI:10.1016/j.bmcl.2013.10.060 · 2.65 Impact Factor
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ABSTRACT: PEGylation is the covalent conjugation of PEG to therapeutic molecules. Protein PEGylation is a clinically proven approach for extending the circulation half-life and reducing the immunogenicity of protein therapeutics. Most clinically used PEGylated proteins are heterogeneous mixtures of PEG positional isomers conjugated to different residues on the protein main chain. Current research is focused to reduce product heterogeneity and to preserve bioactivity. Recent advances and possible future directions in PEGylation are described in this review. So far protein PEGylation has yielded more than 10 marketed products and in view of the lack of equally successful alternatives to extend the circulation half-life of proteins, PEGylation will still play a major role in drug delivery for many years to come.Future medicinal chemistry 10/2014; 6(16):1829-46. DOI:10.4155/fmc.14.125 · 4.00 Impact Factor
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ABSTRACT: A robust convergent synthesis of the prodrugs of HCV replicase inhibitors (1-5) is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a -hydrazinoester, generated in situ from the bis-BOC protected precursors (25 or 33). The acidic conditions not only released the otherwise unstable -hydrazinoesters but also were the key to avoid the facile decarboxylation to the parent drugs from the carboxylic ester prodrugs (1-5). The bis-BOC -hydrazinoesters (25 and 33) were prepared by addition of ester enolates (from 23 and 32) to di-t-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde (20) from the diol (27).The Journal of Organic Chemistry 10/2013; 78(23). DOI:10.1021/jo4014595 · 4.64 Impact Factor