Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.

Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket and optimization of the P(1)' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P(4)-capped inhibitors were also found to have improved PK profile.

The structures of both native and S139A holo-HCV NS3/4A protease domain were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contributions to the binding energy arise from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease, which is currently in clinical trials.

The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

ChemInformVolume 35, Issue 16 Natural Products Preparation of (2,2-Dimethylhexahydrofuro[2,3-c]pyrrol-6-yl)methanol (I): A Conformationally Restricted Congener of Nonproteinogenic 3-Hydroxy-4-methylproline. Edwin Jao, Edwin Jao Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this authorStephane Bogen, Stephane Bogen Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this authorAnil K. Saksena, Anil K. Saksena Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this authorViyyoor Girijavallabhan, Viyyoor Girijavallabhan Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this author Edwin Jao, Edwin Jao Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this authorStephane Bogen, Stephane Bogen Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this authorAnil K. Saksena, Anil K. Saksena Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this authorViyyoor Girijavallabhan, Viyyoor Girijavallabhan Schering-Plough Res. Inst., Kenilworth, NJ 07033, USASearch for more papers by this author First published: 25 March 2004 https://doi.org/10.1002/chin.200416164Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Edwin Jao, Stephane Bogen, Anil K. Saksena, Viyyoor Girijavallabhan, Preparation of (2,2-Dimethylhexahydrofuro[2,3-c]pyrrol-6-yl)methanol (I): A Conformationally Restricted Congener of Nonproteinogenic 3-Hydroxy-4-methylproline., Synthesis, 2003, 2643–2646. 10.1055/s-2003-42426 CASWeb of Science®Google Scholar Volume35, Issue16April 20, 2004 ReferencesRelatedInformation