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Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality 1 , 2 , 3 . Current interferon-based therapies 4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics 5 , 6 . The HCV-encoded NS3 protease is essential for viral replication 7 , 8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

We have developed a convergent and stereoselective synthesis of orally active renin inhibitor BILA 2157 BS . Three building blocks were used to generate the basic skeleton of the inhibitor. The key feature consisted of the late elaboration of the 2-amino-4-thiazolyl heterocycle from a vinylbromide precursor. The synthetic sequence, which required a total of 22 chemical steps, provided 0.6 kg of BILA 2157 BS in 7.3% overall yield.Key words: renin, inhibitor, peptidomimetic, stereoselective synthesis.