Hepatitis C virus NS3/4a protease inhibitors.

Hepatitis C virus (HCV) infection is a major health issue around the world and HCV NS3/4a protease inhibitors have been the focus of intensive research for the past 20 years. From the first identification of substrate-derived peptide inhibitors to the complex, macrocyclic compounds, including paritaprevir and grazoprevir, that are currently available, the field has used structure-based design to confront the issues of potency, resistance and pharmacokinetics. Numerous breakthrough structures from a multitude of companies have led to compounds that are now key components of combination therapies with cure rates of >90%. Herein, we detail the compounds that have advanced to clinical trials including their design and their impact on the NS3/4a protease field.

[1]  L. Vrang,et al.  In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor , 2009, Antimicrobial Agents and Chemotherapy.

[2]  Brad J. Wood,et al.  Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study , 2015, The Lancet.

[3]  Brian L. Pearlman,et al.  Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study , 2014, The Lancet.

[4]  Steven R. LaPlante,et al.  An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus , 2003, Nature.

[5]  Qihong Huang,et al.  A Twenty-Eight-Day Mechanistic Time Course Study in the Rhesus Monkey with Hepatitis C Virus Protease Inhibitor BILN 2061 , 2011, Toxicologic pathology.

[6]  R. Cortese,et al.  Potent peptide inhibitors of human hepatitis C virus NS3 protease are obtained by optimizing the cleavage products. , 1998, Biochemistry.

[7]  T. Asselah,et al.  Fibrosis and disease progression in hepatitis C , 2002, Hepatology.

[8]  M. Katharine Holloway,et al.  Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease. , 2008, Journal of the American Chemical Society.

[9]  B. Brandhuber,et al.  Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior. , 2009, Biochemistry.

[10]  T. Berg,et al.  Expert opinion on the treatment of patients with chronic hepatitis C , 2009, Journal of viral hepatitis.

[11]  Bin Wang,et al.  Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease. , 2014, Journal of medicinal chemistry.

[12]  J. G. Taylor,et al.  GS‐9857 in patients with chronic hepatitis C virus genotype 1–4 infection: a randomized, double‐blind, dose‐ranging phase 1 study , 2016, Journal of viral hepatitis.

[13]  Adam T. Gates,et al.  MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants , 2012, Antimicrobial Agents and Chemotherapy.

[14]  M. Rudd,et al.  Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. , 2010, Journal of medicinal chemistry.

[15]  V. de Lédinghen,et al.  Multicenter Experience with Boceprevir or Telaprevir to Treat Hepatitis C Recurrence after Liver Transplantation: When Present Becomes Past, What Lessons for Future? , 2015, PloS one.

[16]  D. Hazuda,et al.  Sustained Viral Response in a Hepatitis C Virus-Infected Chimpanzee via a Combination of Direct-Acting Antiviral Agents , 2010, Antimicrobial Agents and Chemotherapy.

[17]  Tom Chu,et al.  Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial , 2010, The Lancet.

[18]  A. Molla,et al.  In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450 , 2014, Antimicrobial Agents and Chemotherapy.

[19]  Rebecca T. Ruck,et al.  Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor. , 2016, ACS medicinal chemistry letters.

[20]  A. Good,et al.  Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection. , 2014, Journal of medicinal chemistry.

[21]  T. Asselah,et al.  Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial , 2015, The Lancet.

[22]  A. Kwong,et al.  Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease. , 2006, Infectious disorders drug targets.

[23]  B. Samuelsson,et al.  Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. , 2014, Journal of medicinal chemistry.

[24]  D. Lavanchy,et al.  The global burden of hepatitis C , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[25]  M. Rudd,et al.  Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor. , 2012, ACS medicinal chemistry letters.

[26]  M. Houghton,et al.  Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. , 1989, Science.

[27]  Jean-Michel Pawlotsky,et al.  Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs in Interferon-Free Regimens. , 2016, Gastroenterology.

[28]  R. D. de Knegt,et al.  Pharmacokinetics and Antiviral Activity of Phx1766, a Novel HCV Protease Inhibitor, Using An Accelerated Phase I Study Design , 2012, Antiviral therapy.

[29]  C. Rice,et al.  Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites , 1993, Journal of virology.

[30]  A. Agarwal,et al.  Rapid and Sharp Decline in HCV upon Monotherapy with Ns3 Protease Inhibitor, Ach-1625 , 2012, Antiviral therapy.

[31]  Catherine Caillet,et al.  Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320. , 2015, Bioorganic & medicinal chemistry letters.

[32]  Qi Gao,et al.  The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection. , 2014, Journal of medicinal chemistry.

[33]  M. Murcko,et al.  Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4A Cofactor Peptide , 1996, Cell.

[34]  Weiying Yang,et al.  Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: , 2006, Journal of medicinal chemistry.

[35]  Qian Huang,et al.  P2‐Quinazolinones and Bis‐Macrocycles as New Templates for Next‐Generation Hepatitis C Virus NS3/4a Protease Inhibitors: Discovery of MK‐2748 and MK‐6325 , 2015, ChemMedChem.

[36]  Charles M. Rice,et al.  Unravelling hepatitis C virus replication from genome to function , 2005, Nature.

[37]  T. Hassanein,et al.  Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study , 2015, The Lancet.

[38]  M. Garneau,et al.  Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335). , 2010, Journal of medicinal chemistry.

[39]  Weiying Yang,et al.  Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor. , 2010, ACS medicinal chemistry letters.

[40]  J. Kort,et al.  Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection , 2015, Antimicrobial Agents and Chemotherapy.

[41]  W. Delaney,et al.  Discovery of GS-9256: a novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity. , 2012, Bioorganic & medicinal chemistry letters.

[42]  Tara L. Kieffer,et al.  Hepatitis C virus drug resistance–associated substitutions: State of the art summary , 2015, Hepatology.

[43]  K. Reddy,et al.  GrazoprevirElbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection , 2015, Annals of Internal Medicine.

[44]  P. Simmonds,et al.  Genetic diversity and evolution of hepatitis C virus--15 years on. , 2004, The Journal of general virology.

[45]  Bradley C Doak,et al.  How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets. , 2016, Journal of medicinal chemistry.

[46]  D. Lamarre,et al.  Peptide-based inhibitors of the hepatitis C virus serine protease. , 1998, Bioorganic & medicinal chemistry letters.

[47]  T. Appleby,et al.  Discovery of GS-9451: an acid inhibitor of the hepatitis C virus NS3/4A protease. , 2012, Bioorganic & medicinal chemistry letters.

[48]  M. Rudd,et al.  Bismacrocyclic inhibitors of hepatitis C NS3/4a protease. , 2008, Angewandte Chemie.

[49]  O. Weiland,et al.  ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. , 2014, Gastroenterology.