WO1998046630A1 - Inhibiteurs de protease ns3 pour l'hepatite c - Google Patents

Inhibiteurs de protease ns3 pour l'hepatite c Download PDF

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Publication number
WO1998046630A1
WO1998046630A1 PCT/GB1998/001126 GB9801126W WO9846630A1 WO 1998046630 A1 WO1998046630 A1 WO 1998046630A1 GB 9801126 W GB9801126 W GB 9801126W WO 9846630 A1 WO9846630 A1 WO 9846630A1
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Prior art keywords
hydrophobe
angstroms
negative
features
feature
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Application number
PCT/GB1998/001126
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English (en)
Inventor
Terance Hart
Martin Quibell
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Peptide Therapeutics Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peptide Therapeutics Limited filed Critical Peptide Therapeutics Limited
Priority to EP98917395A priority Critical patent/EP0975662A1/fr
Priority to JP54364898A priority patent/JP2001521516A/ja
Priority to AU70635/98A priority patent/AU7063598A/en
Publication of WO1998046630A1 publication Critical patent/WO1998046630A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to inhibitors of hepatitis C NS3 protease, compounds which fit the pharmacophoric profiles of these inhibitors and use of these inhibitors for the treatment of hepatitis C.
  • NASH non- A non-B hepatitis
  • HCV hepatitis C virus
  • NANBH. 1,2 Upon first exposure to HCV approximately 2-% of infected individuals develop acute clinical hepatitis while others appear to resolve spontaneously. However, in most instances the virus establishes a chrome infection which persists for decades. 4 This situation usually results in recurrent and progressively worsening liver inflammation, often leading to more severe disease states such as cirrhosis and hepatocellular carcinoma. 3
  • the HCV vi ⁇ on has a positive strand RNA genome that contains a single large open reading frame encoding a polyprotem of 3010-3033 ammo acid residues.
  • the nonstructural proteins involved in replication of the HCV genome are released by the action of two protemases; NS2-3 and NS3.
  • the action of NS3 protease yields the nonstructural proteins NS4A, NS4B, NS5A and NS5B.
  • N-termmal domain of NS3 contains a trypsin-hke se ⁇ ne protease and the catalytic triad of H ⁇ s-57, Asp-81 and Ser- 139 (numbe ⁇ ng from the start of NS3) are strictly conserved among all HCV de ⁇ ved sequences. It is thought that, because the NS3 protease is essential for viral replication, then inhibitors of this enzyme will be useful m the treatment of NANBH disease.
  • the invention provides novel inhibitors of hepatitis C NS3 protease.
  • the invention provides compounds which fit a pharmacopho ⁇ c profile of a hepatitis C NS3 protease inhibitor.
  • the invention provides use of inhibitors of the invention for the treatment of hepatitis C.
  • the invention provides use of the inhibitors of the invention m the manufacture of a medicament for the treatment of hepatitis C.
  • the present invention provides a composition which comp ⁇ ses a pharmaceutically acceptable amount of an inhibitor of the invention together with a pharmaceutically acceptable earner or diluent.
  • Figure 1 shows a first pharmacophoric profile of a substrate of hepatitis C NS3 protease.
  • Figure 2 shows the distance and angle constraints of the pharmacopho ⁇ c profile of figure 1.
  • Figure 3 shows a second pharmacophoric profile of a substrate of hepatitis C NS3 protease.
  • Figures 4 and 5 show the distance and angle constraints of the pharmacopho ⁇ c profile of figure 3.
  • Figure 6 shows a third pharmacopho ⁇ c profile of a substrate of hepatitis C NS3 protease.
  • Figure 7 shows the distance and angle constraints of the pharmacopho ⁇ c profile of figure 6.
  • Figure 8 shows an example of a compound which fits the pharmacopho ⁇ c profile of figure 1.
  • Figure 9 shows an example of a compound which fits the pharmacophoric profile of figure 3.
  • Figure 10 shows an example of a compound which fits the pharmacopho ⁇ c profile of figure 6.
  • Pu ⁇ fied insoluble NS3 protease (15.6 mg/m m 8 M urea) was obtained from the Hepatitis C J8 strain. Refolding of the NS3 protease was earned out by dilution of the 5 protein to 100 nM into 50 mM Tns-HCl; pH 7.4 containing 10 mM CHAPS
  • the depsipeptide compounds were synthesised in parallel fashion using Fmoc-Rmk- DA/MDA denvatised macrocrowns (ex Chiron Mimotopes, Australia) loaded at approximately 7 ⁇ M per crown. Prior to synthesis each crown was connected to its respective stems and slotted into the 8 x 12 stem holder. Coupling of the ammo acids employed standard Fmoc ammo acid chemistry as desc ⁇ bed in 'Solid Phase Peptide Synthesis', E. Atherton and R.C. Sheppard, IRL Press Ltd, Oxford, UK, 1989.
  • a 250 ml solvent resistant bath is charged with 200 ml of a 20% pipendme/DMF solution.
  • the multipm assembly is added and deprotection allowed to proceed for 30 minutes.
  • the assembly is then removed and excess solvent removed by bnef shaking
  • the assembly is then washed consecutively with (200 ml each), DMF (5 minutes) and MeOH (5 minutes, 2 minutes, 2 minutes) and left to air dry for 15 minutes.
  • a 1 cm path length UV cell is charged with 1.2 ml of a 20% pipendme/DMF solution and used to zero the absorbance of the UV spectrometer at a wavelength of 290nm.
  • Coupling of Standard Ammo Acid Residues are performed by charging the approp ⁇ ate wells of a polypropylene 96 well plate with the pattern of activated solutions required du ⁇ ng a particular round of coupling. Macrocrown (approx 7 ⁇ mole) standard couplings are performed in DMF (500 ⁇ l).
  • the appropnate N ⁇ -Fmoc ammo acid pfp esters (10 equivalents calculated from the loading of each crown) and HOBt (10 equivalents) required for the particular round of coupling are accurately weighed into suitable containers.
  • the approp ⁇ ate N ⁇ -Fmoc ammo acids (10 equivalents calculated from the loading of each crown), desired coupling agent e.g. HBTU (9.9 equivalents calculated from the loading of each crown) and activation e.g. HOBt (9.9 equivalents calculated from the loading of each crown), NMM (19.9 equivalents calculated from the loading of each crown) are accurately weighed into suitable containers.
  • the protected and activated Fmoc ammo acid denvatives are then dissolved in DMF (500 ⁇ l for each macrocrown e.g. for 20 macrocrowns, 20 x 10 eq. x 7 ⁇ moles of denvative would be dissolved m 10 ml DMF).
  • the approp ⁇ ate derivatives are then dispensed to the appropnate wells ready for commencement of the 'coupling cycle'. As a standard, coupling reactions are allowed to proceed for 6 hours. The coupled assembly was then washed as detailed below.
  • L-lactic acid (lOeq per macrocrown) and HOBt (lOeq per macrocrown) were dissolved m dichloromethane (450 ⁇ L per macrocrown) and cooled with ⁇ ce-st ⁇ rnng to 0°C.
  • Diisopropylcarbodiamide (lOeq per macrocrown) m dichloromethane (50 ⁇ L per macrocrown) was added and the mixture stirred at 0°C for lhr.
  • Fmoc-Abu-F (lOeq per macrocrown) was dissolved in dichloromethane (450 ⁇ L per well) and the pin assembly for esterification soaked in the acid fluoride solution for 5mins. 4- dimethylaminopyridine (2eq per macrocrown) in dichloromethane (50 ⁇ L per macrocrown) was added to each well and the reaction left at RT for lhr followed by washing as detailed below.
  • Acid mediated cleavage protocols are strictly performed in a fume hood.
  • a polystyrene 96 well plate (1 ml/well) is labelled, then the tare weight measured to the nearest mg.
  • Appropriate wells are then charged with a trifluoroacetic acid/triisopropylsilane (95:5, v/v, 600 ⁇ l) cleavage solution, in a pattern corresponding to that of the multipin assembly to be cleaved.
  • the multipin assembly is added, the entire construct covered in tin foil and left for 2 hours.
  • the multipin assembly is then added to another polystyrene 96 well plate (1 ml/well) containing trifluoroacetic acid/triisopropylsilane (95:5, v/v, 600 ⁇ l) (as above) for 5 minutes. Work up of Cleaved Peptides
  • the primary polystyrene cleavage plate (2 hour cleavage) and the secondary polystyrene plate (5 minute wash) are then placed in the SpeedVac and the solvents removed (minimum drying rate) for 90 minutes.
  • the contents of the secondary polystyrene plate are transferred to their corresponding wells on the primary plate using an acetonitrile/water/acetic acid (50:45:5, v/v/v) solution (3 x 150 ⁇ l) and the spent secondary plate discarded.
  • a 5 ⁇ L aliquot from each well is diluted to 100 ⁇ l with 0.1% aq. TFA, then a 10 ⁇ L aliquot from this plate diluted with a further 100 ⁇ l 0.1% aq. TFA.
  • the double diluted plate is analysed by HPLC-MS.
  • the plate is covered with tin foil, held to the plate with an elastic band.
  • a pin prick is placed in the foil directly above each well and the plate placed at -80°C for 30 minutes.
  • the plate is then lyophilised on the 'Heto freeze drier' overnight.
  • Inhibitors of the protease were synthesised according to the route shown in scheme 2.
  • the Fmoc-Rink-DA/MDA macrocrowns are assembled (simply clipped) onto stems and slotted into the 8 x 12 stem holder m the 5 desired pattern for synthesis.
  • a 250 ml solvent resistant bath is charged with 200 ml of a 20% pipendme/DMF solution.
  • the multipm assembly is added and deprotection allowed to proceed for 30 minutes.
  • the assembly is then removed and excess solvent removed by brief shaking.
  • the 0 assembly is then washed consecutively with (200 ml each), DMF (5 minutes) and MeOH
  • a 1 cm path length UV cell is charged with 1.2 ml of a 20% pipendme/DMF solution and used to zero the absorbance of the UV spectrometer at a wavelength of 290nm.
  • the amines were dissolved in DMF /!% AcOH( 450 ⁇ L per well) and dispensed into approp ⁇ ate wells. The p assembly was then added and left for 5 minutes. After this time Na(AcO) 3 BH (lOeq per well in lOO ⁇ L DMF per well) was added and the reaction left 4hrs with occasional agitation to remove any gas bubbles formed.
  • the pm assembly was removed from the plate, shaken free of excess liquid then immersed m DMF / H 2 0 (200mL, 9.1 , v/v) for 5mms.
  • the acetate salt was neutralised by treatment of the pm assembly with 20% pipe ⁇ dine / DMF (200mL. v/v) for 30mms.
  • the assembly was shaken then immersed DMF (200mL) for 5mms, then MeOH (200mL, 3 x 5mms) and allowed to air dry.
  • Coupling reactions are performed by charging the approp ⁇ ate wells of a polypropylene 96 well plate with the pattern of activated solutions required du ⁇ ng a particular round of coupling. Macrocrown (approx 7 ⁇ mole) standard couplings are performed m DMF (500 ⁇ l).
  • the approp ⁇ ate N ⁇ -Fmoc ammo acid pfp esters (10 equivalents calculated from the loading of each crown) and HOBt (10 equivalents) required for the particular round of coupling are accurately weighed into suitable containers.
  • the approp ⁇ ate N ⁇ -Fmoc ammo acids (10 equivalents calculated from the loading of each crown), desired coupling agent e.g. HBTU (9.9 equivalents calculated from the loading of each crown) and activation e.g. HOBt (9.9 equivalents calculated from the loading of each crown), NMM (19.9 equivalents calculated from the loading of each crown) are accurately weighed into suitable containers.
  • the protected and activated Fmoc ammo acid de ⁇ vatives are then dissolved m DMF (500 ⁇ l for each macrocrown e.g. for 20 macrocrowns, 20 x 10 eq. x 7 ⁇ moles of de ⁇ vative would be dissolved 10 000 ⁇ l DMF).
  • the approp ⁇ ate denvatives are then dispensed to the appropnate wells ready for commencement of the 'coupling cycle'. As a standard, coupling reactions are allowed to proceed for 6 hours. The coupled assembly was then washed as detailed below.
  • the multipm assembly is bnefly shaken to remove excess solvent washed consecutively with (200 ml each), MeOH (5 minutes) and DMF (5 minutes) and de-protected (see 6.2). If the multipm assembly is to be stored or reacted further, then a full washing cycle consisting bnef shaking then consecutive washes with (200 ml each), DMF (5 minutes) and MeOH (5 minutes, 2 minutes, 2 minutes) is performed.
  • Benzoic Anhydride (20eq) is dissolved in DMF (500 ⁇ l for each macrocrown e.g. for 20 macrocrowns, 20 x 10 eq. x 7 ⁇ moles of de ⁇ vative would be dissolved m 10 000 ⁇ l DMF) to which NMM (40eq) was added.
  • the solution is then dispensed to the approp ⁇ ate wells ready for commencement of the 'coupling cycle '.
  • the reaction was then left for 2 hours.
  • the coupled assembly was then washed as detailed below and treated with 20% pipe ⁇ dine in DMF followed by the standard washing cycle before cleavage. Following these general methods, the single peptide inhibitors shown in Table 2 were sequentially assembled by applying the approp ⁇ ate coupling procedure at the correct cycle dunng synthesis.
  • Acid mediated cleavage protocols are stnctly performed m a fume hood.
  • a polystyrene 96 well plate (1 ml/well) is labelled, then the tare weight measured to the nearest mg.
  • Approp ⁇ ate wells are then charged with a trifluoroacetic acid/t ⁇ isopropylsilane (95:5, v/v, 600 ⁇ l) cleavage solution, m a pattern corresponding to that of the multipm assembly to be cleaved.
  • the multipm assembly is added, the entire construct covered in tin foil and left for 2 hours.
  • the multipm assembly in then added to another polystyrene 96 well plate (1 ml/well) containing trifluoroacetic acid/tnisopropylsilane (95:5, v/v, 600 ⁇ l) (as above) for 5 minutes.
  • the pnmary polystyrene cleavage plate (2 hour cleavage) and the secondary polystyrene plate (5 mmute wash) are then placed m the GeneVac and the solvents, no heating required.
  • the contents of the secondary polystyrene plate are transferred to their corresponding wells on the primary plate using an acetonitrile/water/acetic acid (50:45:5, v/v/v) solution (3 x 150 ⁇ l) and the spent secondary plate discarded.
  • a 5 ⁇ L aliquot from each well is diluted to 100 ⁇ l with 0.1% aq. TFA, then a lO ⁇ L aliquot from this plate diluted with a further 100 ⁇ l 0.1% aq. TFA.
  • the double diluted plate is analysed by HPLC-MS.
  • the plate is covered with tm foil, held to the plate with an elastic band. A pm p ⁇ ck is placed m the foil directly above each well and the plate placed at -80°C for 30 minutes. The plate is then lyophihsed on the ⁇ eto freeze dner' overnight. Finally, the dned plate is weighed. The total cleaved peptide is quantified (by weight) and 5 the average content of each peptide calculated. Since all the peptides present have ongmated from the same peptide-pm assembly, cleaved under identical conditions, it is reasonable to assume that the contents of each well are roughly eqmmolar.
  • Collections of compounds with biological activity for HCV NS3 J8 are provided as training sets. Each compound m a training set undergoes full conformational analysis 12 . A representative number of conformers are generated over a given energy range above the lowest energy conformation 13 M
  • This information is used to derive a pharmacophore (based on seven chemical feature type rules) 15 that correlates to the observed biological activity. It is assumed that the molecules m a training set all act at the same target m the same manner of action.
  • a HYDROPHOBE feature is defined as
  • this may also include residues which have a partial hydrophobic character such as Lysyl or Glutammyl ammo acid sidechains.
  • a NEGATIVE IOMZABLE feature is defined as
  • a RING AROMATIC feature is defined as
  • a pharmacophore* consisting of at least the following chemical features can be used to desc ⁇ be MOTIF 1 •
  • HYDROPHOBE Three HYDROPHOBE" features and a NEGATIVE IONIZABLE feature. 15
  • the HYDROPHOBE features are represented by spheres 1 7 Angstroms radius
  • the NEGATIVE IONIZABLE feature is similarly represented by a sphere 1.7 Angstroms radius (up to 2.7 Angstroms)
  • Negative Iomzable 1 has Cartesian XYZ co-ordmates of -8.207, -3.059, -3.78
  • Hydrophobe 2 has co-ordinates of -2.975, 4.725, -0.229
  • Hydrophobe 3 has co-ordinates of 6.065, 2.205, 3.991
  • Hydrophobe 4 has co-ordmates of 3.385, -2.935, -1.149
  • the term "pharmacophore” is not meant to imply any pharmacological activity.
  • the term refers to those chemical features and their distnbution m three-dimensional space which constitute and epitomise the preferred requirements for molecular interaction with the receptor.
  • the receptor being the catalytic active site of the protease HCV NS3 J8.
  • a pharmacophore consisting of at least the following chemical features can be used to desc ⁇ be MOTIF 2:
  • the HYDROPHOBE features are represented by spheres 1.7 Angstroms radius (up to 2.7 Angstroms).
  • the NEGATIVE IONIZABLE feature is similarly represented by a sphere 1.7 Angstroms radius (up to 2.7 Angstroms).
  • the RING AROMATIC is represented as two equal size spheres (1.6 Angstroms radius up to 2.0 Angstoms) whose centroids are 3.1 Angstroms apart. One sphere corresponds to the position of an aromatic ring moiety and the other to the projected point of the electron pi stacking of the aromatic ⁇ ng system.
  • Negative Iomzable 1 has Cartesian XYZ co-ordinates of 4.907, -1.284, 3.039 * Hydrophobe 2 has co-ordmates of 1.496, 3.212, -3.793
  • Hydrophobe 3 has co-ordinates of -4.324, -4.228, -3.313
  • Ring Aromatic centroid 4 has co-ordmates of -0.798, - 1.230, 2.330
  • Ring Aromatic projected point 5 has co-ordmates of -4.324, -4.228, -3.313
  • the tolerances on all distances between these features is +/- 0.5 Angstroms and the geomet ⁇ c angles +/- 20 Degrees.
  • a pharmacophore consisting of at least the following chemical features can be used to describe MOTIF 3:
  • the HYDROPHOBE features are represented by spheres 1.7 Angstroms radius (up to 2.7 Angstroms).
  • the NEGATIVE IONIZABLE features are similarly represented by spheres 1.7 Angstroms radius (up to 2.7 Angstroms).
  • Negative Iomzable 1 has Cartesian XYZ co-ordmates of -8.551, 0.769, -0.895
  • Hydrophobe 2 has co-ordmates of -0.697, 1.087, -5.655
  • Negative Iomzable 3 has co-ordinates of 6.098, 1.653, 4.709
  • Hydrophobe 4 has co-ordmates of 0.503, -2.453, 2.784
  • the compounds of the invention may essentailly consist of an ammo acid (aa) sequence (or non peptide mimetic thereof) or may include a sequence corresponding to one of the pharmacophoric motifs described herein.
  • aa ammo acid
  • the sequence might consist of or include the sequence [aa] n wherein n is any integer from 4 upwards, for example wherein n is 4,5,6,7,8,9,10,11 or 12.

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Abstract

L'invention concerne un profil pharmacophore spécifique qui représente la structure correspondant aux inhibiteurs de protéase NS3 pour l'hépatite C. Les résultats d'études de localisation de l'enzyme conduites avec des substrats de type depsipeptide permettent d'élaborer un profil de liaison pharmacophore spécifique. On a établi que les composés ayant un tel motif étaient des inhibiteurs de protéase NS3 pour l'hépatite C. Ces inhibiteurs sont utilisés pour le traitement de l'hépatite C.
PCT/GB1998/001126 1997-04-16 1998-04-16 Inhibiteurs de protease ns3 pour l'hepatite c WO1998046630A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP98917395A EP0975662A1 (fr) 1997-04-16 1998-04-16 Inhibiteurs de protease ns3 pour l'hepatite c
JP54364898A JP2001521516A (ja) 1997-04-16 1998-04-16 Ｃ型肝炎ｎｓ３プロテアーゼインヒビター
AU70635/98A AU7063598A (en) 1997-04-16 1998-04-16 Hepatitis c ns3 protease inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9707659.0A GB9707659D0 (en) 1997-04-16 1997-04-16 Hepatitis C NS3 Protease inhibitors
GB9707659.0 1997-04-16

Publications (1)

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WO1998046630A1 true WO1998046630A1 (fr) 1998-10-22

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PCT/GB1998/001126 WO1998046630A1 (fr) 1997-04-16 1998-04-16 Inhibiteurs de protease ns3 pour l'hepatite c

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EP (1) EP0975662A1 (fr)
JP (1) JP2001521516A (fr)
AU (1) AU7063598A (fr)
GB (1) GB9707659D0 (fr)
WO (1) WO1998046630A1 (fr)

Cited By (91)

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US6143715A (en) * 1997-08-11 2000-11-07 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptide analogues
WO2002018369A2 (fr) 2000-08-31 2002-03-07 Eli Lilly And Company Inhibiteurs peptidomimetiques de protease
WO2002057425A2 (fr) 2001-01-22 2002-07-25 Merck & Co., Inc. Derives de nucleoside comme inhibiteurs de l'arn polymerase virale arn-dependante
WO2002079234A1 (fr) * 2001-03-29 2002-10-10 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Peptides et utilisation de ceux-ci en tant qu'inhibiteurs de la protease ns3 du virus de l'hepatite c
WO2003062267A2 (fr) * 2002-01-17 2003-07-31 Amura Therapeutics Limited Substrats pour la surveillance d'une activite enzymatique
US6608027B1 (en) 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
US6642204B2 (en) 2002-02-01 2003-11-04 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
US6767991B1 (en) 1997-08-11 2004-07-27 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptides
US6846806B2 (en) 2000-10-23 2005-01-25 Bristol-Myers Squibb Company Peptide inhibitors of Hepatitis C virus NS3 protein
US6869964B2 (en) 2002-05-20 2005-03-22 Bristol-Myers Squibb Company Heterocyclicsulfonamide hepatitis C virus inhibitors
US6878722B2 (en) 2002-05-20 2005-04-12 Bristol-Myers Squibb Company Substituted cycloalkyl P1′ hepatitis C virus inhibitors
WO2005037214A2 (fr) 2003-10-14 2005-04-28 Intermune, Inc. Acylsulfonamides et acides carboxyliques macrocycliques utilises en tant qu'inhibiteurs de la replication du virus de l'hepatite c
US6909000B2 (en) 2001-07-11 2005-06-21 Vertex Pharmaceuticals Incorporated Bridged bicyclic serine protease inhibitors
WO2005123087A2 (fr) 2004-06-15 2005-12-29 Merck & Co., Inc. Analogues nucleosidiques de c-purine, servant d'inhibiteurs d'arn-polymerase virale arn-dependante
WO2006012078A2 (fr) 2004-06-24 2006-02-02 Merck & Co., Inc. Phosphoramidates d'aryle nucleosidiques pour le traitement d'infection virale arn dependante de l'arn
US6995174B2 (en) 2002-05-20 2006-02-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7041698B2 (en) 2002-05-20 2006-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7091184B2 (en) 2002-02-01 2006-08-15 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
US7119072B2 (en) 2002-01-30 2006-10-10 Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the hepatitis C virus
US7122627B2 (en) 1999-07-26 2006-10-17 Bristol-Myers Squibb Company Lactam inhibitors of Hepatitis C virus NS3 protease
US7132504B2 (en) 2003-11-12 2006-11-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7135462B2 (en) 2003-11-20 2006-11-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
JP2006526011A (ja) * 2003-04-11 2006-11-16 バーテックス　ファーマシューティカルズ　インコーポレイテッド セリンプロテアーゼ（特に、ｈｃｖｎｓ３−ｎｓ４ａプロテアーゼ）のインヒビター
WO2007015855A1 (fr) 2005-07-20 2007-02-08 Merck & Co., Inc. Inhibiteurs de la protease ns3 du vhc
WO2007021610A2 (fr) 2005-08-09 2007-02-22 Merck & Co., Inc. Derives d'acetaux cycliques de ribonucleosides pour traiter une infection virale d'arn arn dependante
WO2007044893A2 (fr) 2005-10-11 2007-04-19 Intermune, Inc. Composés et méthodes pour l'inhibition de la réplication du virus de l'hépatite c
WO2007059221A2 (fr) 2005-11-11 2007-05-24 Vertex Pharmaceuticals, Inc Variantes du virus de l'hepatite c
US7241796B2 (en) 2001-10-24 2007-07-10 Vertex Pharmaceuticals Inc. Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
US7273885B2 (en) 2002-04-11 2007-09-25 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
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EP0975662A1 (fr) 2000-02-02

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