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  • In summary we have designed


    In summary, we have designed and explored synthetic routes towards novel acylsulfamoyl benzoxaborole-based HCV NS3 protease inhibitors. Interestingly, the resulting, unoptimized P1–P3 and P2–P4 macrocyclic inhibitors were equipotent in an enzyme assay and somewhat less potent in replicon assays, compared to danoprevir. Further optimization of the benzoxaborole moiety may allow to rebalance the physicochemical properties (e.g., MW, PSA) of the resulting compounds and improve their membrane absorption, potency and bioavailability. In addition, it will be interesting to examine the HCV protease inhibitor resistance profiles of these compounds due to the anticipated additional interactions of P1′ benzoxaborole with the enzyme active site as shown in . Acknowledgments
    Hepatitis C virus is the primary etiological agent responsible for non-A, non B infections of the liver. The prognosis for patients infected with hepatitis C is poor with a majority of these infections turning chronic progressing to cirrhosis of the liver and hepatocellular carcinoma. Pegylated alpha-interferon in combination with ribivirin is the primary standard of care which is effective in ∼50% of genotype-1 infected patients. Patients infected with genotype-2 respond better to Pegylated alpha-interferon with >80% of patients demonstrating sustained reduction in viral RNA. Lack of effective methods to treat genotype-1 infections and patients relapsing from interferon therapy necessitate discovery of new drugs. Significant efforts are now directed towards development of therapies that target key ag1478 vital for HCV replication and maturation. Hepatitis C virus is a positive strand virus that encodes a single polyprotein of ∼3000 amino acids. This polyprotein which contains all the structural and functional proteins is post translationally modified by HCV NS3 protease. This enzyme with the assistance of cofactor NS4B catalyzes the cleavage of NS2–NS3, NS3–NS4A, NS4A–NS5B junctions to form functional proteins. HCV NS3, a serine protease has a shallow active site on the surface of the enzyme catalyzes the cleavage of cysteine–serine or a cysteine–threonine bond. Inhibition of this vital enzyme has been extensively investigated in an effort to develop potential drugs for the treatment of HCV infections. Boceprevir and VX-950 are two ketoamide derived inhibitors that have been advanced to Phase-III clinical trails and demonstrated excellent efficacy in humans. In addition, macrocyclic inhibitors ITMN-191, MK7006 and TMC435350 have also been progressed to clinical studies and have demonstrated excellent viral load reduction in patients. These compounds are currently being evaluated at various phases of clinical development. Boceprevir () is a ketoamide containing inhibitor that readily epimerizes in human serum under physiological conditions at the P center. The ()-diastereomer at this center is the more potent isomer whereas the ()-isomer is less active. Several attempts to avoid this epimerization by introduction of quaternary amino acids have resulted in significant loss in potency. A recent publication from a group at Boehringer Ingelhiem demonstrated that novel hydrazide derived inhibitor spanning from P to demonstrated excellent enzyme binding (). However these compounds were peptidic and no cellular activity in the replicon based assay was reported. From our experience in developing ketoamide derived clinical candidate , we discovered appropriate modifications of P, P and P moieties allowed truncation of inhibitors spanning from P to achieving compounds with lower molecular weights, desirable binding and pharmacokinetic profile. In this present work we envisioned that introduction of hydrazide analogs in our class of inhibitors may potentially provide compounds with better binding than and compounds with desirable cellular activity. In addition these modifications would depeptidize our compounds and provide inhibitors that are free of labile stereocenters which epimerized under physiological conditions. Pursuant to our identification of we had also discovered that introduction of novel depeptidized P caps allowed improvement in binding and cellular activity of In this Letter we disclose our efforts to identify novel hydrazide derived inhibitors with excellent binding and cellular activity.