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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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WO
WIPO (PCT)
Prior art keywords
hydrophobe
angstroms
negative
features
feature
Prior art date
Application number
PCT/GB1998/001126
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English (en)
Inventor
Terance Hart
Martin Quibell
Original Assignee
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 JP54364898A priority Critical patent/JP2001521516A/ja
Priority to EP98917395A priority patent/EP0975662A1/fr
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
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
EP98917395A EP0975662A1 (fr) 1997-04-16 1998-04-16 Inhibiteurs de protease ns3 pour l'hepatite c
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
GB9707659.0 1997-04-16
GBGB9707659.0A GB9707659D0 (en) 1997-04-16 1997-04-16 Hepatitis C NS3 Protease inhibitors

Publications (1)

Publication Number Publication Date
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7309708B2 (en) 2003-11-20 2007-12-18 Birstol-Myers Squibb Company Hepatitis C virus inhibitors
BG65356B1 (bg) * 1999-04-06 2008-03-31 Boehringer Ingelheim (Canada) Ltd. Макроциклени пептиди, активни срещу вируса на хепатит с, фармацевтични състави, които ги съдържат, методи за получаване и използването им
US7378422B2 (en) 2003-09-05 2008-05-27 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
EP1944042A1 (fr) 2003-10-27 2008-07-16 Vertex Pharmceuticals Incorporated Combinaisons pour le traitement HCV
US7494660B2 (en) 2003-10-27 2009-02-24 Vertex Pharmaceuticals Incorporated HCV NS3-NS4A protease resistance mutants
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7511157B2 (en) 2004-07-20 2009-03-31 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor dipeptide analogs
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
EP2103623A2 (fr) 2005-07-25 2009-09-23 Intermune, Inc. Nouveaux inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US7696242B2 (en) 2004-07-20 2010-04-13 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor peptide analogs
US7705138B2 (en) 2005-11-11 2010-04-27 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
EP2194043A2 (fr) 2005-08-19 2010-06-09 Vertex Pharmceuticals Incorporated Procédés et intermédiaires
US7749961B2 (en) 2004-01-21 2010-07-06 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
WO2010082050A1 (fr) 2009-01-16 2010-07-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Composés benzoxazocines substitués 7-aminoalkyle macrocycycliques destinés au traitement des infections par hépatite c
WO2010084115A2 (fr) 2009-01-20 2010-07-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Agents antiviraux
US7767660B2 (en) 2006-12-20 2010-08-03 Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
US7781422B2 (en) 2006-12-20 2010-08-24 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
EP2256113A1 (fr) 2005-08-02 2010-12-01 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases
US7879797B2 (en) 2005-05-02 2011-02-01 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
WO2011014487A1 (fr) 2009-07-30 2011-02-03 Merck Sharp & Dohme Corp. Inhibiteurs de protéase ns3 du virus de l'hépatite c
WO2011034518A1 (fr) 2009-09-15 2011-03-24 Taigen Biotechnology Co., Ltd. Inhibiteurs de protéases de vhc
EP2311851A2 (fr) 2004-02-04 2011-04-20 Vertex Pharmaceuticals Incorporated Inhibitoren der Serinproteasen, insbesondere der HCV-NS3-NS4A-Protease
US7973040B2 (en) 2008-07-22 2011-07-05 Merck Sharp & Dohme Corp. Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
US7989438B2 (en) 2007-07-17 2011-08-02 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Therapeutic compounds
WO2011091757A1 (fr) 2010-01-27 2011-08-04 AB Pharma Ltd. Composés polyhétérocycliques hautement puissants en tant qu'inhibiteurs du vhc
EP2361925A1 (fr) 2003-10-10 2011-08-31 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases, en particulier la HCV NS3-NS4A protéase
EP2364984A1 (fr) 2005-08-26 2011-09-14 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases,
EP2374464A2 (fr) 2004-10-01 2011-10-12 Vertex Pharmaceuticals Incorporated Inhibition de la protéase N3S-NS4A du virus de l'hépatite C
EP2399575A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés, utilisations et compositions pour le traitement d'une infection par un virus de la famille de Flaviviridae par l'inhibition de récepteur farnésoïde X (FXR)
US8101595B2 (en) 2006-12-20 2012-01-24 Istituto di Ricerche di Biologia Molecolare P. Angletti SpA Antiviral indoles
US8138164B2 (en) 2006-10-24 2012-03-20 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8178491B2 (en) 2007-06-29 2012-05-15 Gilead Sciences, Inc. Antiviral compounds
US8178520B2 (en) 2006-05-15 2012-05-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Macrocyclic compounds as antiviral agents
US8183216B2 (en) 2007-09-24 2012-05-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Nucleoside derivatives as inhibitors of viral polymerases
US8187874B2 (en) 2003-10-27 2012-05-29 Vertex Pharmaceuticals Incorporated Drug discovery method
WO2012107589A1 (fr) 2011-02-11 2012-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement et la prévention des infections à vhc
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8278322B2 (en) 2005-08-01 2012-10-02 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8309540B2 (en) 2006-10-24 2012-11-13 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8314062B2 (en) 2006-06-23 2012-11-20 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic compounds as antiviral agents
US8377873B2 (en) 2006-10-24 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8377874B2 (en) 2006-10-27 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8399615B2 (en) 2005-08-19 2013-03-19 Vertex Pharmaceuticals Incorporated Processes and intermediates
WO2013074386A2 (fr) 2011-11-15 2013-05-23 Merck Sharp & Dohme Corp. Inhibiteurs de la protéase ns3 du vhc
US8461107B2 (en) 2008-04-28 2013-06-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
WO2013106344A1 (fr) 2012-01-12 2013-07-18 Ligand Pharmaceuticals, Inc. Nucléosides 2'-c-méthyl comprenant un diester de phosphate cyclique de 1,3-propanediol (2-oxo-[1,3,2]-dioxaphosphorinane à la position 5'
US8513186B2 (en) 2007-06-29 2013-08-20 Gilead Sciences, Inc. Antiviral compounds
WO2014123794A1 (fr) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
WO2014123795A2 (fr) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
US8927569B2 (en) 2007-07-19 2015-01-06 Merck Sharp & Dohme Corp. Macrocyclic compounds as antiviral agents
US8962810B2 (en) 2011-06-16 2015-02-24 AB Pharma Ltd. Macrocyclic heterocyclic compound for inhibiting hepatitis C virus and preparation and use thereof
EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
US9738661B2 (en) 2006-10-27 2017-08-22 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013904A1 (fr) * 1990-03-05 1991-09-19 Cephalon, Inc. Proteases analogues a la chymotrypsine et leurs inhibiteurs
WO1997008304A2 (fr) * 1995-08-22 1997-03-06 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Methode de production, de purification et d'analyse de polypeptides par l'activite proteolytique de la vhc ns3 protease
WO1998017679A1 (fr) * 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, notamment de ns3 protease du virus de l'hepatite c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991013904A1 (fr) * 1990-03-05 1991-09-19 Cephalon, Inc. Proteases analogues a la chymotrypsine et leurs inhibiteurs
WO1997008304A2 (fr) * 1995-08-22 1997-03-06 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Methode de production, de purification et d'analyse de polypeptides par l'activite proteolytique de la vhc ns3 protease
WO1998017679A1 (fr) * 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibiteurs de serines proteases, notamment de ns3 protease du virus de l'hepatite c

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MIN CHU ET AL: "STRUCTURE OF SCH 68631: A NEW HAPATITIS C VIRUS PROTEINASE INHIBITOR FROM STREPTOMYCES SP", TETRAHEDRON LETTERS, vol. 37, no. 40, 30 September 1996 (1996-09-30), pages 7229 - 7232, XP000627717 *
STEINKUHLER C ET AL: "IN VITRO ACTIVITY OF HEPATITIS C VIRUS PROTEASE NS3 PURIFIED FROM RECOMBINANT BACULOVIRUS-INFECTED SF9 CELLS", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 271, no. 11, 15 March 1996 (1996-03-15), pages 6367 - 6373, XP002018451 *

Cited By (140)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6143715A (en) * 1997-08-11 2000-11-07 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptide analogues
US6767991B1 (en) 1997-08-11 2004-07-27 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptides
US6608027B1 (en) 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
BG65356B1 (bg) * 1999-04-06 2008-03-31 Boehringer Ingelheim (Canada) Ltd. Макроциклени пептиди, активни срещу вируса на хепатит с, фармацевтични състави, които ги съдържат, методи за получаване и използването им
US7122627B2 (en) 1999-07-26 2006-10-17 Bristol-Myers Squibb Company Lactam inhibitors of Hepatitis C virus NS3 protease
EP2368878A1 (fr) 2000-08-31 2011-09-28 Vertex Pharmaceuticals Incorporated Inhibiteurs de protéase peptidomimétique
EP2368877A1 (fr) 2000-08-31 2011-09-28 Vertex Pharmaceuticals Incorporated Intermédiaires chiraux pour la préparation des Inhibiteurs de protéase peptidomimétique
WO2002018369A2 (fr) 2000-08-31 2002-03-07 Eli Lilly And Company Inhibiteurs peptidomimetiques de protease
EP2371839A1 (fr) 2000-08-31 2011-10-05 Vertex Pharmaceuticals Incorporated Inhibiteurs de prothèse peptidominétique
EP1878720A1 (fr) 2000-08-31 2008-01-16 Vertex Pharmaceuticals Incorporated Procédé pour la préparation des bicycloprolinates chiraux utiles dans la préparation des inhibiteurs de protéase peptidominétique
EP2368901A1 (fr) 2000-08-31 2011-09-28 Vertex Pharmaceuticals Incorporated Inhibiteurs de protéase peptidomimétique
DE20122915U1 (de) 2000-08-31 2010-04-08 Vertex Pharmaceuticals Inc., Cambridge Peptidomimetika als Protease Inhibitoren
US6939854B2 (en) 2000-10-23 2005-09-06 Bristol-Myers Squibb Pharma Company Peptide inhibitors of hepatitis C virus NS3 protease
US6846806B2 (en) 2000-10-23 2005-01-25 Bristol-Myers Squibb Company Peptide inhibitors of Hepatitis C virus NS3 protein
EP2360166A1 (fr) 2001-01-22 2011-08-24 Merck Sharp & Dohme Corp. Dérivés de nucléosides en tant qu'inhibiteurs de polymérase virale d'ARN dépendante de l'ARN
EP2399588A1 (fr) 2001-01-22 2011-12-28 Merck Sharp & Dohme Corp. Dérivés de nucléosides en tant qu'inhibiteurs de polymérase virale d'ARN dépendante de l'ARN
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
US7119073B2 (en) 2001-03-29 2006-10-10 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Peptides and their use as inhibitors of hepatitis C virus ns3 protease
US6909000B2 (en) 2001-07-11 2005-06-21 Vertex Pharmaceuticals Incorporated Bridged bicyclic serine protease inhibitors
US8486989B2 (en) 2001-10-24 2013-07-16 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
EP2402009A1 (fr) 2001-10-24 2012-01-04 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases, en particulier de la protéase NS3-NS4A du virus de l'hépatite C, intégrant un système de cycle fusionné
US7241796B2 (en) 2001-10-24 2007-07-10 Vertex Pharmaceuticals Inc. Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
WO2003062267A3 (fr) * 2002-01-17 2003-09-04 Amura Therapeutics Ltd Substrats pour la surveillance d'une activite enzymatique
WO2003062267A2 (fr) * 2002-01-17 2003-07-31 Amura Therapeutics Limited Substrats pour la surveillance d'une activite enzymatique
US7119072B2 (en) 2002-01-30 2006-10-10 Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the hepatitis C virus
US7091184B2 (en) 2002-02-01 2006-08-15 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
US6642204B2 (en) 2002-02-01 2003-11-04 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor tri-peptides
JP2009185081A (ja) * 2002-04-11 2009-08-20 Vertex Pharmaceut Inc 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
EP2468744A2 (fr) 2002-04-11 2012-06-27 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases, en particulier la HCV NS3-NS4A protéase
JP2010241821A (ja) * 2002-04-11 2010-10-28 Vertex Pharmaceut Inc 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
US7273885B2 (en) 2002-04-11 2007-09-25 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
US7041698B2 (en) 2002-05-20 2006-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
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
US6995174B2 (en) 2002-05-20 2006-02-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
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
JP2011068655A (ja) * 2003-04-11 2011-04-07 Vertex Pharmaceuticals Inc 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
US7939667B2 (en) 2003-05-21 2011-05-10 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US7585845B2 (en) 2003-05-21 2009-09-08 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US8067438B2 (en) 2003-05-21 2011-11-29 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US7378422B2 (en) 2003-09-05 2008-05-27 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
US7745444B2 (en) 2003-09-05 2010-06-29 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
EP2573083A1 (fr) 2003-09-05 2013-03-27 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases, en particulier la HCV NS3-NS4A protéase
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2361925A1 (fr) 2003-10-10 2011-08-31 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases, en particulier la HCV NS3-NS4A protéase
EP2407470A2 (fr) 2003-10-14 2012-01-18 F. Hoffmann-La Roche Ltd. Acylsulfonamides et acides carboxyliques macrocycliques utilisés en tant qu'inhibiteurs de la réplication du virus de l'hépatite C
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
EP1944042A1 (fr) 2003-10-27 2008-07-16 Vertex Pharmceuticals Incorporated Combinaisons pour le traitement HCV
US7494660B2 (en) 2003-10-27 2009-02-24 Vertex Pharmaceuticals Incorporated HCV NS3-NS4A protease resistance mutants
US8187874B2 (en) 2003-10-27 2012-05-29 Vertex Pharmaceuticals Incorporated Drug discovery method
US7884199B2 (en) 2003-10-27 2011-02-08 Vertex Pharmaceuticals Incorporated HCV NS3-NS4 protease resistance mutants
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
US7309708B2 (en) 2003-11-20 2007-12-18 Birstol-Myers Squibb Company Hepatitis C virus inhibitors
US7749961B2 (en) 2004-01-21 2010-07-06 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2311851A2 (fr) 2004-02-04 2011-04-20 Vertex Pharmaceuticals Incorporated Inhibitoren der Serinproteasen, insbesondere der HCV-NS3-NS4A-Protease
US7666855B2 (en) 2004-02-13 2010-02-23 Metabasis Therapeutics, Inc. 2′-C-methyl nucleoside derivatives
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
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
US7696242B2 (en) 2004-07-20 2010-04-13 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor peptide analogs
US7511157B2 (en) 2004-07-20 2009-03-31 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor dipeptide analogs
US7767818B2 (en) 2004-07-20 2010-08-03 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor dipeptide analogs
EP2374464A2 (fr) 2004-10-01 2011-10-12 Vertex Pharmaceuticals Incorporated Inhibition de la protéase N3S-NS4A du virus de l'hépatite C
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
US7879797B2 (en) 2005-05-02 2011-02-01 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8216999B2 (en) 2005-07-20 2012-07-10 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
WO2007015855A1 (fr) 2005-07-20 2007-02-08 Merck & Co., Inc. Inhibiteurs de la protease ns3 du vhc
EP2305698A2 (fr) 2005-07-25 2011-04-06 Intermune, Inc. Inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
EP2305695A2 (fr) 2005-07-25 2011-04-06 Intermune, Inc. Inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
EP2305696A2 (fr) 2005-07-25 2011-04-06 Intermune, Inc. Inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
EP2103623A2 (fr) 2005-07-25 2009-09-23 Intermune, Inc. Nouveaux inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
EP2305697A2 (fr) 2005-07-25 2011-04-06 Intermune, Inc. Inhibiteurs macrocycliques de la multiplication du virus de L'Hépatite C
US8278322B2 (en) 2005-08-01 2012-10-02 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
EP2256113A1 (fr) 2005-08-02 2010-12-01 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases
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
US8399615B2 (en) 2005-08-19 2013-03-19 Vertex Pharmaceuticals Incorporated Processes and intermediates
EP2364970A1 (fr) 2005-08-19 2011-09-14 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires
EP2194043A2 (fr) 2005-08-19 2010-06-09 Vertex Pharmceuticals Incorporated Procédés et intermédiaires
EP2357170A1 (fr) 2005-08-19 2011-08-17 Vertex Pharmaceuticals Incorporated Procédés et intermédiaires
US8871904B2 (en) 2005-08-19 2014-10-28 Vertex Pharmaceuticals Incorporated Processes and intermediates
US8637457B2 (en) 2005-08-19 2014-01-28 Vertex Pharmaceuticals Incorporated Processes and intermediates
US7776887B2 (en) 2005-08-19 2010-08-17 Vertex Pharmaceuticals Incorporated Processes and intermediates
EP2364984A1 (fr) 2005-08-26 2011-09-14 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases,
EP2366704A1 (fr) 2005-08-26 2011-09-21 Vertex Pharmaceuticals Incorporated Inhibiteurs de sérine protéases,
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
US7705138B2 (en) 2005-11-11 2010-04-27 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
EP2392588A2 (fr) 2005-11-11 2011-12-07 Vertex Pharmaceuticals Incorporated Variantes du virus de l'hépatite C
EP2392590A2 (fr) 2005-11-11 2011-12-07 Vertex Pharmaceuticals Incorporated Variantes du virus de l'hépatite C
EP2392589A2 (fr) 2005-11-11 2011-12-07 Vertex Pharmaceuticals Incorporated Variantes du virus de l'hépatite C
WO2007059221A2 (fr) 2005-11-11 2007-05-24 Vertex Pharmaceuticals, Inc Variantes du virus de l'hepatite c
US8501450B2 (en) 2005-11-11 2013-08-06 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
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
US8178520B2 (en) 2006-05-15 2012-05-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Macrocyclic compounds as antiviral agents
US8314062B2 (en) 2006-06-23 2012-11-20 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic compounds as antiviral agents
EP2399575A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés, utilisations et compositions pour le traitement d'une infection par un virus de la famille de Flaviviridae par l'inhibition de récepteur farnésoïde X (FXR)
EP2399988A2 (fr) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Système de culture cellulaire pour la réplication du virus de l'hépatite C par l'activation ou l'inhibition de récepteur farnésoïde X (FXR) et méthode de diagnostic pour l'infection avec VHC
US8138164B2 (en) 2006-10-24 2012-03-20 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8377873B2 (en) 2006-10-24 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8309540B2 (en) 2006-10-24 2012-11-13 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8377874B2 (en) 2006-10-27 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US9738661B2 (en) 2006-10-27 2017-08-22 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8101595B2 (en) 2006-12-20 2012-01-24 Istituto di Ricerche di Biologia Molecolare P. Angletti SpA Antiviral indoles
US7767660B2 (en) 2006-12-20 2010-08-03 Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
US7781422B2 (en) 2006-12-20 2010-08-24 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8513186B2 (en) 2007-06-29 2013-08-20 Gilead Sciences, Inc. Antiviral compounds
US8178491B2 (en) 2007-06-29 2012-05-15 Gilead Sciences, Inc. Antiviral compounds
US8809266B2 (en) 2007-06-29 2014-08-19 Gilead Sciences, Inc. Antiviral compounds
US8809267B2 (en) 2007-06-29 2014-08-19 Gilead Sciences, Inc. Antiviral compounds
US7989438B2 (en) 2007-07-17 2011-08-02 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Therapeutic compounds
US8927569B2 (en) 2007-07-19 2015-01-06 Merck Sharp & Dohme Corp. Macrocyclic compounds as antiviral agents
US8183216B2 (en) 2007-09-24 2012-05-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Nucleoside derivatives as inhibitors of viral polymerases
US8461107B2 (en) 2008-04-28 2013-06-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
EP2540349A1 (fr) 2008-07-22 2013-01-02 Merck Sharp & Dohme Corp. Compositions pharmaceutiques comprenant un composé de quinoxaline macrocyclique qui est un inhibiteur de la protéase HCV NS3
EP2540350A1 (fr) 2008-07-22 2013-01-02 Merck Sharp & Dohme Corp. Combinaisons d'un composé de quinoxaline macrocyclique qui est un des inhibiteurs de la protéase HCV NS3 avec d'autres agents HCV
US7973040B2 (en) 2008-07-22 2011-07-05 Merck Sharp & Dohme Corp. Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors
US8080654B2 (en) 2008-07-22 2011-12-20 Insituto di Ricerche di Biologia Molecolare P. Angeletti SpA Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors
WO2010082050A1 (fr) 2009-01-16 2010-07-22 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Composés benzoxazocines substitués 7-aminoalkyle macrocycycliques destinés au traitement des infections par hépatite c
WO2010084115A2 (fr) 2009-01-20 2010-07-29 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Agents antiviraux
US8828930B2 (en) 2009-07-30 2014-09-09 Merck Sharp & Dohme Corp. Hepatitis C virus NS3 protease inhibitors
WO2011014487A1 (fr) 2009-07-30 2011-02-03 Merck Sharp & Dohme Corp. Inhibiteurs de protéase ns3 du virus de l'hépatite c
WO2011034518A1 (fr) 2009-09-15 2011-03-24 Taigen Biotechnology Co., Ltd. Inhibiteurs de protéases de vhc
WO2011091757A1 (fr) 2010-01-27 2011-08-04 AB Pharma Ltd. Composés polyhétérocycliques hautement puissants en tant qu'inhibiteurs du vhc
WO2012107589A1 (fr) 2011-02-11 2012-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes et compositions pharmaceutiques pour le traitement et la prévention des infections à vhc
US8962810B2 (en) 2011-06-16 2015-02-24 AB Pharma Ltd. Macrocyclic heterocyclic compound for inhibiting hepatitis C virus and preparation and use thereof
WO2013074386A2 (fr) 2011-11-15 2013-05-23 Merck Sharp & Dohme Corp. Inhibiteurs de la protéase ns3 du vhc
US9328138B2 (en) 2011-11-15 2016-05-03 Msd Italia S.R.L. HCV NS3 protease inhibitors
WO2013106344A1 (fr) 2012-01-12 2013-07-18 Ligand Pharmaceuticals, Inc. Nucléosides 2'-c-méthyl comprenant un diester de phosphate cyclique de 1,3-propanediol (2-oxo-[1,3,2]-dioxaphosphorinane à la position 5'
WO2014123795A2 (fr) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
WO2014123794A1 (fr) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Composés hétérocycliques tétracycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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GB9707659D0 (en) 1997-06-04
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AU7063598A (en) 1998-11-11

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