Nathalie Goudreau

Summary

Affiliation: Boehringer Ingelheim

Publications

  1. pmc Molecular mechanism by which a potent hepatitis C virus NS3-NS4A protease inhibitor overcomes emergence of resistance
    Jeff A O'Meara
    Boehringer Ingelheim Canada Limited, Research and Development, Laval, Quebec H7S 2G5, Canada
    J Biol Chem 288:5673-81. 2013
  2. doi request reprint A strategy to reduce biliary clearance in early drug discovery
    Nathalie Rioux
    Department of Biological Sciences, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada Electronic address
    J Pharmacol Toxicol Methods 68:346-8. 2013
  3. doi request reprint Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype
    Pierre L Beaulieu
    Medicinal Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
    Bioorg Med Chem Lett 23:4132-40. 2013
  4. doi request reprint Synthesis and optimization of a novel series of HCV NS3 protease inhibitors: 4-arylproline analogs
    François Bilodeau
    Boehringer Ingelheim Canada Ltd, Research and Development, 2100 rue Cunard, Laval, Quebec, Canada H7S 2G5
    Bioorg Med Chem Lett 23:4267-71. 2013
  5. doi request reprint Discovery and structural characterization of a new inhibitor series of HIV-1 nucleocapsid function: NMR solution structure determination of a ternary complex involving a 2:1 inhibitor/NC stoichiometry
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, QC, Canada H7S 2G5
    J Mol Biol 425:1982-98. 2013
  6. doi request reprint A novel inhibitor-binding site on the HIV-1 capsid N-terminal domain leads to improved crystallization via compound-mediated dimerization
    Christopher T Lemke
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
    Acta Crystallogr D Biol Crystallogr 69:1115-23. 2013
  7. ncbi request reprint A systematic approach to the optimization of substrate-based inhibitors of the hepatitis C virus NS3 protease: discovery of potent and specific tripeptide inhibitors
    Montse Llinas-Brunet
    Department of Chemistry, Research and Development, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada
    J Med Chem 47:6584-94. 2004
  8. doi request reprint Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)
    Montse Llinas-Brunet
    Department of Medicinal Chemistry, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
    J Med Chem 53:6466-76. 2010
  9. doi request reprint Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    ACS Chem Biol 8:1074-82. 2013
  10. pmc Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335
    Christopher T Lemke
    Boehringer Ingelheim Canada Ltd, Research and Development, Laval, Quebec, Canada
    J Biol Chem 286:11434-43. 2011

Collaborators

Detail Information

Publications27

  1. pmc Molecular mechanism by which a potent hepatitis C virus NS3-NS4A protease inhibitor overcomes emergence of resistance
    Jeff A O'Meara
    Boehringer Ingelheim Canada Limited, Research and Development, Laval, Quebec H7S 2G5, Canada
    J Biol Chem 288:5673-81. 2013
    ..In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms...
  2. doi request reprint A strategy to reduce biliary clearance in early drug discovery
    Nathalie Rioux
    Department of Biological Sciences, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada Electronic address
    J Pharmacol Toxicol Methods 68:346-8. 2013
    ..This study proposes a strategy to reduce biliary clearance using the efflux ratio in Caco-2 cells in parallel to an abbreviated pharmacokinetic study in bile duct-cannulated rats (BDC)...
  3. doi request reprint Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype
    Pierre L Beaulieu
    Medicinal Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
    Bioorg Med Chem Lett 23:4132-40. 2013
    ..The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. ..
  4. doi request reprint Synthesis and optimization of a novel series of HCV NS3 protease inhibitors: 4-arylproline analogs
    François Bilodeau
    Boehringer Ingelheim Canada Ltd, Research and Development, 2100 rue Cunard, Laval, Quebec, Canada H7S 2G5
    Bioorg Med Chem Lett 23:4267-71. 2013
    ..The impact of this systematic SAR on different drug properties is reported. ..
  5. doi request reprint Discovery and structural characterization of a new inhibitor series of HIV-1 nucleocapsid function: NMR solution structure determination of a ternary complex involving a 2:1 inhibitor/NC stoichiometry
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, QC, Canada H7S 2G5
    J Mol Biol 425:1982-98. 2013
    ..In addition, analysis of the interaction details between the inhibitor molecules and NC demonstrated how this novel inhibitor series is mimicking the guanosine nucleobases found in many reported complex structures...
  6. doi request reprint A novel inhibitor-binding site on the HIV-1 capsid N-terminal domain leads to improved crystallization via compound-mediated dimerization
    Christopher T Lemke
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
    Acta Crystallogr D Biol Crystallogr 69:1115-23. 2013
    ....
  7. ncbi request reprint A systematic approach to the optimization of substrate-based inhibitors of the hepatitis C virus NS3 protease: discovery of potent and specific tripeptide inhibitors
    Montse Llinas-Brunet
    Department of Chemistry, Research and Development, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada
    J Med Chem 47:6584-94. 2004
    ..This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections...
  8. doi request reprint Discovery of a potent and selective noncovalent linear inhibitor of the hepatitis C virus NS3 protease (BI 201335)
    Montse Llinas-Brunet
    Department of Medicinal Chemistry, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada
    J Med Chem 53:6466-76. 2010
    ..Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats...
  9. doi request reprint Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    ACS Chem Biol 8:1074-82. 2013
    ..Despite the negative impact of this finding for drug development, the discovery of multiple inhibitor binding sites on CA(NTD) shows that capsid assembly is much more complex than previously realized...
  10. pmc Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335
    Christopher T Lemke
    Boehringer Ingelheim Canada Ltd, Research and Development, Laval, Quebec, Canada
    J Biol Chem 286:11434-43. 2011
    ....
  11. ncbi request reprint Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1-E2 protein-protein interaction: a combined medicinal chemistry, NMR and computational chemistry approach
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Que, Canada H7S 2G5
    Bioorg Med Chem 15:2690-700. 2007
    ..In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead...
  12. doi request reprint Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 2: structure-activity relationships (SAR) of the C3-phenyl moiety
    Lee D Fader
    Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    Bioorg Med Chem Lett 23:3401-5. 2013
    ..The molecular basis of how compound 27 inhibits mature CA assembly is rationalized using high-resolution structural information. Our understanding of how compound 27 may inhibit immature Gag assembly is also discussed...
  13. doi request reprint Monitoring binding of HIV-1 capsid assembly inhibitors using (19)F ligand-and (15)N protein-based NMR and X-ray crystallography: early hit validation of a benzodiazepine series
    Nathalie Goudreau
    Dept of Chemistry and Biological Sciences, Research and Development, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada
    ChemMedChem 8:405-14. 2013
    ..Based on these results, two conformationally restricted cyclic inhibitors were designed to further validate the possible binding modes. These studies were crucial to early hit confirmation and subsequent lead optimization...
  14. ncbi request reprint NMR structural characterization of peptide inhibitors bound to the Hepatitis C virus NS3 protease: design of a new P2 substituent
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    J Med Chem 47:123-32. 2004
    ....
  15. doi request reprint Use of the fused NS4A peptide-NS3 protease domain to study the importance of the helicase domain for protease inhibitor binding to hepatitis C virus NS3-NS4A
    Diane Thibeault
    Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, QC, Canada H7S 2G5
    Biochemistry 48:744-53. 2009
    ..Thus, the protease domain with the NS4A peptide, in a covalent or noncovalent complex, is a good model for the protease activity of native NS3-NS4A...
  16. doi request reprint Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 1: addressing configurational instability through scaffold modification
    Lee D Fader
    Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    Bioorg Med Chem Lett 23:3396-400. 2013
    ....
  17. ncbi request reprint Novel azapeptide inhibitors of hepatitis C virus serine protease
    Murray D Bailey
    Boehringer Ingelheim Canada Ltd Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    J Med Chem 47:3788-99. 2004
    ..Incorporation of these new aza-amino acyl functionalities in the P1 position provided a handle to probe for new interactions in the S' region of the enzyme...
  18. ncbi request reprint Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based beta-strand mimics
    Nathalie Goudreau
    Department of Chemistry, Boehringer Ingelheim Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    J Org Chem 69:6185-201. 2004
    ..The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed...
  19. doi request reprint Inhibition of HIV-1 capsid assembly: optimization of the antiviral potency by site selective modifications at N1, C2 and C16 of a 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole scaffold
    Martin Tremblay
    Boehringer Ingelheim Canada Ltd, Research and Development, Laval, Quebec, Canada H7S 2G5
    Bioorg Med Chem Lett 22:7512-7. 2012
    ..The X-ray structure of 33 complexed with the capsid N-terminal domain allowed identification of major interactions between the inhibitor and the protein...
  20. ncbi request reprint An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
    Daniel Lamarre
    Department of Biological Sciences Boehringer Ingelheim Canada Ltd, Laval, Quebec, H7S 2G5, Canada
    Nature 426:186-9. 2003
    ..Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics...
  21. doi request reprint Potent triazolyl-proline-based inhibitors of HCV NS3 protease
    Julie Naud
    Boehringer Ingelheim Canada Ltd, Research and Development, 2100 rue Cunard, Laval, QC, Canada
    Bioorg Med Chem Lett 18:3400-4. 2008
    ..Further refinement by the incorporation of an aryl-substituted triazole and replacement of the P1 acid with an acyl sulfonamide ultimately provided inhibitors with interesting cellular activity...
  22. ncbi request reprint Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection
    Youla S Tsantrizos
    Department of Chemistry, Boehringer Ingelheim, Canada, Ltd, Research and Development, 2100 Cunard Street, Laval, PQ H7S 2G5, Canada
    Angew Chem Int Ed Engl 42:1356-60. 2003
  23. ncbi request reprint Discovery of the first series of inhibitors of human papillomavirus type 11: inhibition of the assembly of the E1-E2-Origin DNA complex
    Christiane Yoakim
    Department of Chemistry, Boehringer Ingelheim Canada Ltd, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    Bioorg Med Chem Lett 13:2539-41. 2003
    ..We have discovered a series of inhibitors of the assembly of the HPV11 E1-E2-origin DNA complex, which incorporate an indandione fused to a substituted tetrahydrofuran...
  24. pmc Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein
    Christopher T Lemke
    Department of Chemistry, Research and Development, Laval, Quebec, Canada
    J Virol 86:6643-55. 2012
    ..These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action...
  25. ncbi request reprint The therapeutic potential of NS3 protease inhibitors in HCV infection
    Nathalie Goudreau
    Department of Chemistry, Research and Development, Boehringer Ingelheim Ltd, 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada
    Expert Opin Investig Drugs 14:1129-44. 2005
    ..The impressive reduction of HCV RNA plasma levels observed with two of these inhibitors (ciluprevir and VX-950) in clinical trials has undoubtedly illustrated the potential of this viral enzyme-targeted drug discovery approach...
  26. ncbi request reprint Quantifying trifluoroacetic acid as a counterion in drug discovery by 19F NMR and capillary electrophoresis
    Michael J Little
    Department of Chemistry, Boehringer Ingelheim Canada Limited, Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5
    J Pharm Biomed Anal 43:1324-30. 2007
    ..Furthermore, these methods have been successfully applied in a high-throughput fashion, which is a key feature for general applicability in a pharmaceutical setting...
  27. doi request reprint Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly
    Lee D Fader
    Boehringer Ingelheim Canada Ltd, Research and Development, 2100 Cunard Street, Laval, Que, Canada
    Bioorg Med Chem Lett 21:398-404. 2011
    ..Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity...