WO2002005814A1 - Utilisation des antagonistes des recepteurs d'il-8 dans le traitement des infections virales - Google Patents

Utilisation des antagonistes des recepteurs d'il-8 dans le traitement des infections virales Download PDF

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WO2002005814A1
WO2002005814A1 PCT/US2001/022328 US0122328W WO0205814A1 WO 2002005814 A1 WO2002005814 A1 WO 2002005814A1 US 0122328 W US0122328 W US 0122328W WO 0205814 A1 WO0205814 A1 WO 0205814A1
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viral infection
human
respiratory viral
therapeutic agent
respiratory
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PCT/US2001/022328
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English (en)
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Susan B. Dillon
Ruth Tal-Singer
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Smithkline Beecham Corporation
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Priority to US10/333,095 priority Critical patent/US20040038854A1/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU2001273497A priority patent/AU2001273497A1/en
Priority to JP2002511746A priority patent/JP2004509852A/ja
Priority to IL15392101A priority patent/IL153921A0/xx
Priority to NZ523659A priority patent/NZ523659A/en
Priority to KR10-2003-7000717A priority patent/KR20030019587A/ko
Priority to EP01952777A priority patent/EP1307190A4/fr
Priority to MXPA03000500A priority patent/MXPA03000500A/es
Priority to HU0300754A priority patent/HUP0300754A3/hu
Priority to CA002418162A priority patent/CA2418162A1/fr
Priority to BR0112603-2A priority patent/BR0112603A/pt
Publication of WO2002005814A1 publication Critical patent/WO2002005814A1/fr
Priority to NO20030201A priority patent/NO20030201L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • VIRUS INFECTIONS FIELD OF THE INVENTION This invention relates to the use of IL-8, GRO , GRO ⁇ , GRO ⁇ , NAP-2, and
  • ENA-78 modulators in the treatment of viral infections are ENA-78 modulators in the treatment of viral infections.
  • HRV infects nasal epithelial cells. Recent evidence suggests the virus may also infect bronchial epithelium. Prodromal cold symptoms are apparent within 24 hours post-infection, peak on days 2 through 5, and resolve within 7 to 14 days. However, the effects can be more protracted in some individuals. While the virus may clear, symptoms often persist. Symptoms are believed to arise more from the host's response to infection, than an acute cytotoxic effect, since only a small fraction of upper respiratory epithelial cells are demonstrably infected, and there is minimal epithelial cell damage. Increased intranasal levels of kinins, TL-l, IL-8, IL- 6, B -11, and neutrophils are found in normal individuals infected with rhino viruses.
  • IL-1, JL-6 and B -8 are also produced in response to infection with other respiratory viruses (influenza, respiratory syncytial virus) which can cause the common cold and associated sequelae.
  • Interleukin-8 Interleukin-8
  • NAP-1 neutrophil attractant/activation protein- 1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • T-cell lymphocyte chemotactic factor T-cell lymphocyte chemotactic factor.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-l ⁇ , IL-l ⁇ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M.
  • GRO , GRO ⁇ , GRO ⁇ and NAP-2 also belong to the chemokine family. Like IL-8 these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGSA ⁇ , ⁇ and ⁇ respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the ⁇ -family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor (CXCR2).
  • CXCR2 IL-8 B receptor
  • IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GRO ⁇ have demonstrated T-lymphocytes, and basophilic chemotactic activity.
  • BL-8 can induce histamine release from basophils from both normal and atopic individuals.
  • GRO- ⁇ and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils.
  • IL-8 has also been shown to increase the surface expression of Mac- 1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis.
  • IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the IL-8 ⁇ receptor (CXCR2).
  • CXCR2 IL-8 ⁇ receptor
  • IL-8RA which binds only IL-8 with high affinity
  • 1L-8RB which has high affinity for IL-8 as well as for GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL-8RA which binds only IL-8 with high affinity
  • 1L-8RB which has high affinity for IL-8 as well as for GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • Interference with the biochemical processes of epithelial cells resulting from virus infection represents a viable new therapeutic target for an IL-8 receptor antagonist.
  • the present invention is directed to the novel discovery of treatment of this therapeutic target.
  • the present invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 A or B receptor and which method comprises administering an effective amount of an IL-8 receptor antagonist, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to the use of an IL-8 receptor antagonist for the treatment, including prophylaxis and prevention/reduction of the severity of the underlying condition, of a virus infection including but not limited to human rhinovirus, enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, and adenovirus, in a human in need thereof, which method comprises administering to said human an effective amount of an IL-8 receptor antagonist.
  • IL-8 and other cytokines affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators responsible for the symptoms of many viral infections.
  • the inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these symptoms of respiratory viral infection.
  • the present invention is directed to the treatment of symptoms caused by viral infection in a human which is caused by the human rhinovirus, other enterovirus, coronavirus, herpes viruses, influenza virus, parainfluenza virus, respiratory syncytial virus or an adeno virus.
  • the present invention is directed to respiratory viral infections, which exacerbate underlying chronic conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis. It should also be noted that the respiratory viral infection treated herein may be associated with a secondary bacterial infection, such as otitis media, sinusitis or pneumonia.
  • IL-8 receptor antagonists are useful in the treatment of symptoms associated with respiratory viral infection and prevention/reduction of the severity of exacerbations of underlying conditions, including asthma and otitis media, COPD, sinusitis, chronic bronchitis, etc amongst others.
  • Suitable IL-8 inhibitors are well known in the art, and an assay for determining IL-8 inhibition is also readily available. For instance, see U.S. Patents 5886044,5780483,6005008,5929250, 6015908; 5919776, U.S.
  • Provisional Applications 60/134728,60/136666,60/136665,60/136717,60/136667,60/139675, 60/139680,60/139678,60/139673,60/140024,60/139677,60/139674, 60/140025,60/145756,60/164350,60/186239,60/186183,60/186182, 60/188410,60/188243,60/189176,60/189175,60/189848,60/192132,or 60/196022.
  • the IL-8 receptor antagonist may also be administered with a second therapeutic agent.
  • the second therapeutic agent may be an antiviral agent such as ribavirin, amantidine, rimantidine, relenza, tamiflu, BTA 188, RWJ-270210 (BCX- 1812), sICAM-1, tICAM453, Pleconaril or AG 7088; it may also be an antihistamine, such as Benadryl, chlorpheneramine and salts thereof, brompheneramine or salts thereof, etc, a decongestant, such as phenylpropanolamine and salts thereof, pseudoephedreine or salts thereof; steroids, such as dexamethasone, prednisone, or prednisolone, etc; various antibiotics, such as the quinolones, cephalosporins, ⁇ -lactamase inhibitors, etc.; anti-inflammatory agents, such as CSAIDS, COX-1 or COX-2 inhibitors, ASA, or indomethacin, etc.
  • antiviral agent such as riba
  • FIGURES Figure I - Inhibition of RV or Gro -beta induced calcium mobilization in human neutrophils by CXCR2 antagonist X.
  • Figure II Inhibition of RV-induced chemotaxis of human neutrophils by CXCR2 antagonist X.
  • the present IL-8 receptor antagonist can be used in the manufacture of a medicine for the prophylactic or therapeutic treatment of symtoms or sequelae of viral infection in a human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages, or other chemokines which bind to the IL-8 A or B receptor, also referred to as the type I or type ⁇ receptor.
  • the present invention provides a method of treating a viral infection, wherein the chemokine is one which binds to an IL-8 A or B receptor and which method comprises administering an effective amount of a present inhibitor or a pharmaceutically acceptable salt thereof.
  • the chemokines are IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78.
  • a present IL-8 receptor antagonist or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • This invention also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a present IL-8 receptor antagonist and a pharmaceutically acceptable carrier or diluent.
  • the present IL-8 receptor antagonists, pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, bucolally, parenterally or by inhalation. They may be administered in conventional dosage forms prepared by combining a present compound with standard pharmaceutical carriers according to conventional procedures. They may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,.magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the present antagonists may be administered topically, that is by non- systemic administration.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the ear or nose, solutions or suspensions suitable for inhalation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap
  • a mucilage an oil of natural origin such as almond, corn, arachis, castor or olive oil
  • wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • the present antagonists may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the present antagonists may also be administered by inhalation that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a present antagonist or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a present compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • IL-8, and GRO- ⁇ chemokine inhibitory effects of compounds of the present invention are determined by the following in vitro assay: Receptor Binding Assays:
  • IL-8 human recombinant
  • GRO- ⁇ is obtained from NEN- New England Nuclear. All other chemicals are of analytical grade.
  • High levels of recombinant human IL-8 type ⁇ and ⁇ receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al, Science, 1991, 253, 1278). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour, et ah, J. Biol. Chem.. 249 pp 2195-2205 (1974)).
  • homogenization buffer is changed to lOmM Tris-HCL, lmM MgS0_ ⁇ , 0.5mM EDTA (ethylene-diaminetetra- acetic acid), lmM PMSF ( ⁇ -toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5.
  • Membrane protein concentration is determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays are performed in a 96-well micro plate format.
  • Each reaction mixture contains 125j ⁇ £_8 (0.25 nM) or 125j GRO- ⁇ and 0.5 ⁇ g/mL of IL-8R ⁇ or 1.0 ⁇ g/mL of IL-8R ⁇ membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0, containing 1.2 mM MgSO4, 0.1 mM EDTA, 25 mM Na and 0.03 % CHAPS .
  • drug or compound of interest is added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM.
  • the assay is initiated by addition of
  • ⁇ I-JL-S After 1 hour at room temperature the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/ 0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgSO4, 0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter is then dried and counted on the Betaplate liquid scintillation counter.
  • the recombinant IL-8 R ⁇ , or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 R ⁇ , or Type II, receptor is referred to as the permissive receptor.
  • the in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its entirety.
  • Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1, whose disclosure is incorporated herein by reference in its entirety.
  • the chemoattractants IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ and NAP-2 are placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a 5 uM polycarbonate filter.
  • PMNs 0.88 x 10 6 cells suspended in Ringer's Solution (NaCl 118, KC1 4.56, NaHCO 3 25, KH2PO4 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) are placed in each well of a 96 well plate in a volume of 50 ul.
  • the test compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20ug/ml) and
  • This supernatant is added to a second 96 well plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered saline.
  • the plate is placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min intervals according to the method of Nakajima et al J. Biol. Chem. 2544027 (1979).
  • the amount of Elastase released from the PMNs is calculated by measuring the rate of MeOSuc-Ala- Ala-Pro- Val-AMC degradation.
  • BEAS-2B cells were cultured according to instructions provided by ATCC using BEGM (bronchial epithelial growth media) purchased from Clonetics Corp.
  • BEGM bronchial epithelial growth media
  • HELA cell cultures used for detection and titration of virus, were maintained in Eagle's minimum essential media containing 10% fetal calf serum, 2mM 1-glutamine, and 10 mM HEPES buffer (MEM).
  • Virus yield was also determined from culture supematants using a microtitration assay in HELA cell cultures (Subauste et al, supra 1995). In cultures treated with IL-8 inhibitors, drug was added 30 minutes prior to infection. Stocks of compounds were prepared in DMSO (10 mM drug) and stored at -20°C.
  • IL-8R inhibition For detection of IL-8R inhibition, cultures were incubated in basal media without growth factors and additives to reduce endogenous levels of activated IL-8. Supematants were harvested at various time points after addition of rhinovirus and concentrated. Concentrates were fractionated on Superose 6 columns. Supematants were concetrated >50 fold using an Amicon concetrater with 5,000 mol. wt. cut off. A singel injection (0.5 ml) was applied to a Superose 6 size fractionation column which was eluted at a singel flow rate (0.2 ml/min). 0.5 ml fractions were collaceted and assayed for Ca2 + mobilizing activity in freshly isolated human PMN loaded with FURA-2.
  • human BEAS-2B human epithelial cells produced small quantities of at least three known human chemokines, Gro ⁇ , IL-8 and ENA- 78. When these cells are infected with rhinovirus production of the three ELR chemokines increases 6.6 - 20 fold above resting conditions (Table 1).
  • BEAS-2B supernatant was assayed against other freshly isolated human peripheral cells which express a variety of chemokine receptors including CCR1, CCR2, CCR3 and CCR5.
  • chemokine receptors including CCR1, CCR2, CCR3 and CCR5.
  • IL-8, Gro ⁇ and ENA-78 are not present at significant concentrations to promote
  • BEAS-2B cells produce a variety of ELR chemokines which act through the CXCR2 receptor and which can be blocked by selective CXCR2 antagonist.
  • JJL-8 is present in the supernatant it also is blocked completely by the CXCR2 antagonist. This is improbably do to its low level compared with Gro ⁇ .

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Abstract

L'invention concerne une nouvelle utilisation d'un antagoniste des récepteurs d'IL-8 dans le traitement des infections virales chez l'humain ainsi que de l'aggravation des symptômes qui y sont associés.
PCT/US2001/022328 2000-07-18 2001-07-16 Utilisation des antagonistes des recepteurs d'il-8 dans le traitement des infections virales WO2002005814A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
KR10-2003-7000717A KR20030019587A (ko) 2000-07-18 2001-07-16 바이러스 감염의 치료에 있어서 ｉｌ-8 수용체 길항제의용도
AU2001273497A AU2001273497A1 (en) 2000-07-18 2001-07-16 Use of IL-8 receptor antagonists in the treatment of virus infections
JP2002511746A JP2004509852A (ja) 2000-07-18 2001-07-16 ウイルス感染の治療におけるｉｌ−８受容体アンタゴニストの使用
IL15392101A IL153921A0 (en) 2000-07-18 2001-07-16 Use of il-8 receptor antagonists in the treatment of virus infections
NZ523659A NZ523659A (en) 2000-07-18 2001-07-16 Use of IL-8 receptor antagonists in the treatment of virus infections
US10/333,095 US20040038854A1 (en) 2001-07-16 2001-07-16 Use of il-8 receptor antagonists in the treatment of virus infections
EP01952777A EP1307190A4 (fr) 2000-07-18 2001-07-16 Utilisation des antagonistes des recepteurs d'il-8 dans le traitement des infections virales
CA002418162A CA2418162A1 (fr) 2000-07-18 2001-07-16 Utilisation des antagonistes des recepteurs d'il-8 dans le traitement des infections virales
HU0300754A HUP0300754A3 (en) 2000-07-18 2001-07-16 Use of il-8 receptor antagonists in the treatment of virus infections
MXPA03000500A MXPA03000500A (es) 2000-07-18 2001-07-16 Uso de antagonistas del receptor de isoleucina 8 en el tratamiento de infecciones por virus.
BR0112603-2A BR0112603A (pt) 2000-07-18 2001-07-16 Uso de antagonistas receptores de il-8 no tratamento de infecções por vìrus
NO20030201A NO20030201L (no) 2000-07-18 2003-01-15 Bruk av IL-8 reseptorantagonister ved behandling av virusinfeksjoner

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21905300P 2000-07-18 2000-07-18
US60/219,053 2000-07-18

Publications (1)

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WO2002005814A1 true WO2002005814A1 (fr) 2002-01-24

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PCT/US2001/022328 WO2002005814A1 (fr) 2000-07-18 2001-07-16 Utilisation des antagonistes des recepteurs d'il-8 dans le traitement des infections virales

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EP (1) EP1307190A4 (fr)
JP (1) JP2004509852A (fr)
KR (1) KR20030019587A (fr)
CN (1) CN1449285A (fr)
AR (1) AR033830A1 (fr)
AU (1) AU2001273497A1 (fr)
BR (1) BR0112603A (fr)
CA (1) CA2418162A1 (fr)
CZ (1) CZ2003132A3 (fr)
HU (1) HUP0300754A3 (fr)
IL (1) IL153921A0 (fr)
MX (1) MXPA03000500A (fr)
NO (1) NO20030201L (fr)
NZ (1) NZ523659A (fr)
PL (1) PL365886A1 (fr)
WO (1) WO2002005814A1 (fr)
ZA (1) ZA200300474B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006017505A2 (fr) * 2004-08-04 2006-02-16 Schering Corporation Formulations pharmaceutiques
WO2015173701A3 (fr) * 2014-05-12 2016-02-18 Glaxosmithkline Intellectual Property (No. 2) Limited Compositions pharmaceutiques pour traiter des maladies infecteuses
EP3884932A1 (fr) * 2020-03-26 2021-09-29 Dompe' Farmaceutici S.P.A. Inhibiteurs de cxcl8 pour leur utilisation dans le traitement de la covid-19
WO2021191305A1 (fr) * 2020-03-26 2021-09-30 Dompe' Farmaceutici Spa Inhibiteurs de cxcl8 destinés à être utilisés dans le traitement de la covid-19
EP4008325A1 (fr) * 2020-12-02 2022-06-08 Dompe' Farmaceutici S.P.A. Inhibiteurs de cxcl8 pour leur utilisation dans le traitement de la covid-19

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5547979A (en) * 1992-03-30 1996-08-20 Smithkline Beecham TNF inhibition
US5886044A (en) * 1995-02-17 1999-03-23 Smithkline Beecham Corporation IL-8 receptor antagonists

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3539795A (en) * 1994-08-25 1996-03-14 Medical University Of South Carolina Methods of treating cold symptoms using pentoxifylline
SE9802729D0 (sv) * 1998-08-13 1998-08-13 Astra Pharma Prod Novel Compounds
SE9802937D0 (sv) * 1998-09-01 1998-09-01 Astra Pharma Prod Novel compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5547979A (en) * 1992-03-30 1996-08-20 Smithkline Beecham TNF inhibition
US5886044A (en) * 1995-02-17 1999-03-23 Smithkline Beecham Corporation IL-8 receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1307190A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006017505A2 (fr) * 2004-08-04 2006-02-16 Schering Corporation Formulations pharmaceutiques
WO2006017505A3 (fr) * 2004-08-04 2006-12-14 Schering Corp Formulations pharmaceutiques
WO2015173701A3 (fr) * 2014-05-12 2016-02-18 Glaxosmithkline Intellectual Property (No. 2) Limited Compositions pharmaceutiques pour traiter des maladies infecteuses
EP3884932A1 (fr) * 2020-03-26 2021-09-29 Dompe' Farmaceutici S.P.A. Inhibiteurs de cxcl8 pour leur utilisation dans le traitement de la covid-19
WO2021191305A1 (fr) * 2020-03-26 2021-09-30 Dompe' Farmaceutici Spa Inhibiteurs de cxcl8 destinés à être utilisés dans le traitement de la covid-19
EP4008325A1 (fr) * 2020-12-02 2022-06-08 Dompe' Farmaceutici S.P.A. Inhibiteurs de cxcl8 pour leur utilisation dans le traitement de la covid-19

Also Published As

Publication number Publication date
NZ523659A (en) 2006-01-27
AU2001273497A1 (en) 2002-01-30
JP2004509852A (ja) 2004-04-02
NO20030201L (no) 2003-03-17
CA2418162A1 (fr) 2002-01-24
HUP0300754A3 (en) 2009-03-02
BR0112603A (pt) 2004-08-24
CN1449285A (zh) 2003-10-15
PL365886A1 (en) 2005-01-10
ZA200300474B (en) 2004-08-17
MXPA03000500A (es) 2003-06-24
IL153921A0 (en) 2003-07-31
CZ2003132A3 (cs) 2003-09-17
NO20030201D0 (no) 2003-01-15
AR033830A1 (es) 2004-01-07
EP1307190A1 (fr) 2003-05-07
KR20030019587A (ko) 2003-03-06
HUP0300754A2 (hu) 2003-08-28
EP1307190A4 (fr) 2007-08-22

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