Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.

[1]  B. Clarke.  Molecular virology of hepatitis C virus. , 1997, The Journal of general virology.

[2]  H. Blum,et al.  Hepatitis C: molecular virology and antiviral targets. , 2002, Trends in molecular medicine.

[3]  B. Luxon,et al.  Pegylated interferons for the treatment of chronic hepatitis C infection. , 2002, Clinical therapeutics.

[4]  M. Major,et al.  The molecular virology of hepatitis C , 1997, Hepatology.

[5]  R. Bartenschlager,et al.  Novel cell culture systems for the hepatitis C virus. , 2001, Antiviral research.

[6]  D. Wyss,et al.  Structure, biology, and therapeutic implications of pegylated interferon alpha-2b. , 2002, Current pharmaceutical design.

[7]  J. Hoefs,et al.  Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. , 1998, The New England journal of medicine.

[8]  Nahum Sonenberg,et al.  Hepatitis C therapeutics: current status and emerging strategies , 2002, Nature Reviews Drug Discovery.

[9]  M. A. Gerber.  Relation of hepatitis C virus to hepatocellular carcinoma. , 1993, Journal of hepatology.

[10]  P. Jones,et al.  Pyrrolidine-5,5-trans-lactams. 1. Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease. , 2002, Organic letters.

[11]  C. Rice,et al.  Efficient initiation of HCV RNA replication in cell culture. , 2000, Science.

[12]  A. Kwong,et al.  Hepatitis C virus NS3/4A protease. , 1998, Antiviral research.

[13]  J. Hoofnagle.  Therapy of Viral Hepatitis , 1998, Digestion.

[14]  Aril Frydén,et al.  Randomised, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C , 1998, The Lancet.

[15]  J. Silver,et al.  Replication of Subgenomic Hepatitis C Virus Rnas in a Hepatoma Cell Line , 1999 .

[16]  O. Weiland,et al.  Therapy of hepatitis C: Alpha interferon and ribavirin , 1997, Hepatology.

[17]  C. Rice,et al.  Hepatitis C Virus-Encoded Enzymatic Activities and Conserved RNA Elements in the 3′ Nontranslated Region Are Essential for Virus Replication In Vivo , 2000, Journal of Virology.

[18]  J. Hoofnagle,et al.  Hepatitis C: The clinical spectrum of disease , 1997, Hepatology.

[19]  M. Alter,et al.  Epidemiology of Hepatitis C , 2018, Clinical liver disease.

[20]  William M. Lee,et al.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. , 1998, The New England journal of medicine.