DailyUpdates 22nd March: The global antivirals market is forecast to grow from $8.7bn in 2001 to $14bn in 2007 and the development of therapeutics able to treat chronic hepatitis C (HCV) infection represents one particularly urgent need within the antiviral field. Researchers from Boehringer Ingelheim have recently addressed this unmet need, developing potent inhibitors of HCV NS5B RNA-dependent polymerase 

The global antivirals market is forecast to grow from $8.7bn in 2001 to $14bn in 2007, largely due to the high incidence of viral infections and the inadequate efficacy of the drugs currently available. The patient pool is also increasing with pharmaceutical companies targeting developing countries, thus creating a phenomenal opportunity for new drugs and therapies in the antivirals market. 

According to the Center for Disease Control, nearly four million people are or have been infected with hepatitis C (HCV) in the US alone. As the numbers of newly infected individuals decreases, a greater emphasis is being placed on the development of therapeutics able to treat chronic infection. This field is currently unmet, since present therapies are only partially effective and limited by undesirable side effects. 

The viral serine protease and the RNA-dependent RNA polymerase are the best-studied targets for the development of novel therapeutic agents. These enzymes have been extensively characterized at the biochemical and structural level and thus used to set up screening assays for the identification of selective inhibitors. These efforts lead to the discovery of several classes of compounds with potential antiviral activity. 

Researchers from Boehringer Ingelheim have taken this approach and have consequently described the discovery of benzimidazole 5-carboxamide derivatives from a combinatorial screening library as specific inhibitors of the NS5B RNA-dependent polymerase of the hepatitis C virus (HCV). Initial hit-to-lead activities taking advantage of high-throughput parallel synthetic techniques, identified a 1,2-disubstituted benzimidazole 5-carboxylic acid scaffold as the minimum core for biological activity. Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provided an attractive "drug-like" lead structure for further optimization.

Such optimization has led to an increase in potency of greater than 800-fold. These low-nanomolar inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases and therefore represent candidate future HCV therapeutics.

(source DailyUpdates 22nd March; for full abstracts of the original paper see  Bioorg Med Chem Lett. 2004 Feb 23;14(4):967-71; and Bioorg Med Chem Lett. 2004 Jan 5;14(1):119-24)

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