Literature DB >> 24900304

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.

Michael T Rudd1, John A McCauley1, John W Butcher1, Joseph J Romano1, Charles J McIntyre1, Kevin T Nguyen1, Kevin F Gilbert1, Kimberly J Bush1, M Katharine Holloway1, John Swestock1, Bang-Lin Wan1, Steven S Carroll1, Jillian M DiMuzio1, Donald J Graham1, Steven W Ludmerer1, Mark W Stahlhut1, Christine M Fandozzi1, Nicole Trainor1, David B Olsen1, Joseph P Vacca1, Nigel J Liverton1.   

Abstract

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

Entities:  

Keywords:  HCV; Hepatitis C; NS3/4A; macrocycle; ring-closing metathesis

Year:  2011        PMID： 24900304      PMCID： PMC4017977          DOI： 10.1021/ml1002426

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  29 in total

1.  Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335).

Authors:  Montse Llinàs-Brunet; Murray D Bailey; Nathalie Goudreau; Punit K Bhardwaj; Josée Bordeleau; Michael Bös; Yves Bousquet; Michael G Cordingley; Jiamin Duan; Pat Forgione; Michel Garneau; Elise Ghiro; Vida Gorys; Sylvie Goulet; Ted Halmos; Stephen H Kawai; Julie Naud; Marc-André Poupart; Peter W White
Journal:  J Med Chem       Date:  2010-09-09       Impact factor: 7.446

2.  Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease.

Authors:  Nigel J Liverton; M Katharine Holloway; John A McCauley; Michael T Rudd; John W Butcher; Steven S Carroll; Jillian DiMuzio; Christine Fandozzi; Kevin F Gilbert; Shi-Shan Mao; Charles J McIntyre; Kevin T Nguyen; Joseph J Romano; Mark Stahlhut; Bang-Lin Wan; David B Olsen; Joseph P Vacca
Journal:  J Am Chem Soc       Date:  2008-03-14       Impact factor: 15.419

Review 3.  A review of HCV protease inhibitors.

Authors:  Kevin X Chen; F George Njoroge
Journal:  Curr Opin Investig Drugs       Date:  2009-08

Review 4.  Pathogenesis of hepatitis C-associated hepatocellular carcinoma.

Authors:  T Jake Liang; Theo Heller
Journal:  Gastroenterology       Date:  2004-11       Impact factor: 22.682

5.  Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).

Authors:  Scott D Seiwert; Steven W Andrews; Yutong Jiang; Vladimir Serebryany; Hua Tan; Karl Kossen; P T Ravi Rajagopalan; Shawn Misialek; Sarah K Stevens; Antitsa Stoycheva; Jin Hong; Sharlene R Lim; Xiaoli Qin; Robert Rieger; Kevin R Condroski; Hailong Zhang; Mary Geck Do; Christine Lemieux; Gary P Hingorani; Dylan P Hartley; John A Josey; Lin Pan; Leonid Beigelman; Lawrence M Blatt
Journal:  Antimicrob Agents Chemother       Date:  2008-09-29       Impact factor: 5.191

6.  A time-resolved, internally quenched fluorescence assay to characterize inhibition of hepatitis C virus nonstructural protein 3-4A protease at low enzyme concentrations.

Authors:  Shi-Shan Mao; Jillian DiMuzio; Carolyn McHale; Christine Burlein; David Olsen; Steven S Carroll
Journal:  Anal Biochem       Date:  2007-11-04       Impact factor: 3.365

7.  MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease.

Authors:  Nigel J Liverton; Steven S Carroll; Jillian Dimuzio; Christine Fandozzi; Donald J Graham; Daria Hazuda; M Katherine Holloway; Steven W Ludmerer; John A McCauley; Charles J McIntyre; David B Olsen; Michael T Rudd; Mark Stahlhut; Joseph P Vacca
Journal:  Antimicrob Agents Chemother       Date:  2009-10-19       Impact factor: 5.191

8.  Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.

Authors:  Stephanos J Hadziyannis; Hoel Sette; Timothy R Morgan; Vijayan Balan; Moises Diago; Patrick Marcellin; Giuliano Ramadori; Henry Bodenheimer; David Bernstein; Mario Rizzetto; Stefan Zeuzem; Paul J Pockros; Amy Lin; Andrew M Ackrill
Journal:  Ann Intern Med       Date:  2004-03-02       Impact factor: 25.391

9.  Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.

Authors:  J G McHutchison; S C Gordon; E R Schiff; M L Shiffman; W M Lee; V K Rustgi; Z D Goodman; M H Ling; S Cort; J K Albrecht
Journal:  N Engl J Med       Date:  1998-11-19       Impact factor: 91.245

Review 10.  Control of hepatitis C: a medicinal chemistry perspective.

Authors:  Christopher P Gordon; Paul A Keller
Journal:  J Med Chem       Date:  2005-01-13       Impact factor: 7.446
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  2 in total

1.  A versatile synthesis of substituted isoquinolines.

Authors:  Chong Si; Andrew G Myers
Journal:  Angew Chem Int Ed Engl       Date:  2011-09-09       Impact factor: 15.336

2.  Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

Authors:  Steven Harper; John A McCauley; Michael T Rudd; Marco Ferrara; Marcello DiFilippo; Benedetta Crescenzi; Uwe Koch; Alessia Petrocchi; M Katharine Holloway; John W Butcher; Joseph J Romano; Kimberly J Bush; Kevin F Gilbert; Charles J McIntyre; Kevin T Nguyen; Emanuela Nizi; Steven S Carroll; Steven W Ludmerer; Christine Burlein; Jillian M DiMuzio; Donald J Graham; Carolyn M McHale; Mark W Stahlhut; David B Olsen; Edith Monteagudo; Simona Cianetti; Claudio Giuliano; Vincenzo Pucci; Nicole Trainor; Christine M Fandozzi; Michael Rowley; Paul J Coleman; Joseph P Vacca; Vincenzo Summa; Nigel J Liverton
Journal:  ACS Med Chem Lett       Date:  2012-03-02       Impact factor: 4.345
  2 in total

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