EP0909169A1 - Utilisation medicale - Google Patents

Utilisation medicale

Info

Publication number
EP0909169A1
EP0909169A1 EP97901056A EP97901056A EP0909169A1 EP 0909169 A1 EP0909169 A1 EP 0909169A1 EP 97901056 A EP97901056 A EP 97901056A EP 97901056 A EP97901056 A EP 97901056A EP 0909169 A1 EP0909169 A1 EP 0909169A1
Authority
EP
European Patent Office
Prior art keywords
inhibitor
prophylaxis
human
treatment
compound
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97901056A
Other languages
German (de)
English (en)
Inventor
Gary SmithKline Beecham Pharmaceuticals CHRISTIE
Beverley Jane SmithKline Beecham WESTON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0909169A1 publication Critical patent/EP0909169A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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

  • This invention relates to a medical use and in particular to the use of inhibitors of the formation of soluble human CD23 for the treatment of conditions associated with excess production of soluble CD23 (s-CD23) such as autoimmune disease and allergy.
  • s-CD23 soluble CD23
  • Matrix metalloproteases such as collagenase, stromelysin and gelatinase are known to be involved in connective tissue breakdown.
  • matrix metalloprotease inhibitors include derivatives of hydroxamic acid, phosphonates and thiols.
  • WO 93/20047 discloses various derivatives of hydroxamic acid including those from the following patent publications: USP 4599361, EP-A-0236872, EP-A- 0274453, WO 90/05716, WO 90/05719, WO 91/02716, EP-A-0489577, EP-A- 0489579, EP-A-0497192 and WO 92/13831.
  • CD23 (the low affinity IgE receptor FceRTI, Blast 2), is a 45 kDa type ⁇ integral protein expressed on the surface of a variety of mature cells, including B and T lymphocytes, macrophages, natural killer cells, Langerhans cells, monocytes and platelets (Delespesse et al, Adv Immunol, 42 [1991] 149-191). There is also a CD23- like molecule on eosinophils (Grangette et al, J Immunol, JL42 [1989] 3580-3588). CD23 has been implicated in the regulation of the immune response (Delespesse et al, Immunol Rev, 121 [1992] 77-97).
  • Human CD23 exists as two differentially regulated isoforms, a and b, which differ only in the amino acids at the intracellular N-terminus Ofokota et al, Cell, 5 [ [1988] 611-618). In man the constitutive a isoform is found only on B-lymphocytes, whereas type b, inducible by IL4, is found on all cells capable of expressing CD23.
  • i-CD23 cell bound CD23
  • s- CD23 well-defined soluble fragments
  • S-CD23 has been implicated in the overproduction of IgE, the hallmark of allergic diseases such as extrinsic asthma, rhinitis, allergic conjuctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 3 &, [1993] 421-428).
  • Other biological activities attributed to S-CD23 include the stimulation of B cell growth and the induction of the release of mediators from monocytes.
  • S-CD23 serum of patients having B-chronic lymphocytic leukaemia (Sarfati et al, Blood, 21 [1988] 94-98) and in the synovial fluids of patients with rheumatoid arthritis (Chomarat et al. Arthritis and Rheumarism, 3J_ [1993] 234-242).
  • compounds which inhibit the formation of S-CD23 should have twofold actions of a) enhancing negative feedback inhibition of IgE synthesis by maintaining levels of i-CD23 on the surface of B cells, and b) inhibiting the immunostimulatory cytokine activities of higher molecular weight soluble fragments (Mr 37, 33 and 29 kDa) of S-CD23. It has now surprisingly been found that compounds which inhibit the action of matrix metalloproteases (eg collagenase, stromelysin and gelatinase) are effective inhibitors of the release of human soluble CD23 transfected into mammalian cell culture systems.
  • matrix metalloproteases eg collagenase, stromelysin and gelatinase
  • Inhibitors of the matrix metalloproteases are therefore potentially useful for the treatment or prophylaxis of disorders such as allergy and autoimmune disease in which the overproduction of S-CD23 is implicated.
  • Known classes of matrix metalloprotease inhibitors include derivatives of hydroxamic acid, phosphonic acid and thiols, all of which have been shown to inhibit CD23 proteolysis.
  • the present invention provides the use of certain inhibitors of matrix metalloproteases, for the production of a medicament for the treatment or prophylaxis of disorders such as allergy and autoimmune disease in which the overproduction of S-CD23 is implicated.
  • the ⁇ nv ⁇ ntion prcv ides a method for the treatment or prophylaxis of disorders such as allergy and autoimmune disease in which the overproduction of S-CD23 is implicated, which method comprises the administration of certain inhibitors of matrix metalloproteases, to a human or non-human mammal in need thereof.
  • the matrix metalloprotease inhibitors useful in the present invention are set out in the Table.
  • the matrix metaUoprotease inhibitors menuoned herein may exist in several different isomeric forms, including stereoisomeric forms. Unless specificaUy stated to the contrary herein with respect to particular compounds, all isomers including stereoisomers and mixtures of isomers, such as racemic mixtures, are included within the present invention.
  • the isomers, including stereoisomers, of the matrix metaUoprotease inhibitors of the present invention may be prepared as mixtures of such isomers or as individual isomers.
  • the individual isomers may be prepared by any appropriate method, for example individual stereoisomers may be prepared by stereospec ⁇ c chemical synthesis starting from chiral substrates or by separating mixtures of enantiomers using known methods.
  • matrix metaUoprotease inhibitors are isolated in substantially pure form.
  • matrix metaUoprotease inhibitor and equivalent terms means any compound which inhibits any member of the family of zinc and calcium dependent endopepudases (matrix metalloproteases) that have the abUity to degrade components of the connective tissue matrices.
  • Matrix metaUoprotcases and their inhibition are discussed by inter alia Hooper, FEBS Letters 1994, 354,1-6; Gordon et al., Clinical and Experimental Rheumatology 1993, IKSuppl. 8), S91-S94; Woessner, FASEB 1991, 5, 2145-2154; and Birkedal-Hansen, Critical Reviews in Oral Biology and Medicine 1993, 4(2), 197-250.
  • an inhibitor of the formation of soluble human CD23 such as a matrix metaUoprotease inhibitor, has useful medical properties.
  • the active compounds are administered as pharmaceuticaUy acceptable compositions.
  • compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart failure. Othr-.r alternative modes of administration include sublingual or transdermal administration.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or Uquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycoUate or microcrystaUine ceUulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of f ⁇ Uers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods weU known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral Uquid preparations may be in the form of, for example, emulsions, syrups, or eUxirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylceUulose, carboxymethylceUulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oU, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorb
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions of this invention may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns for example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns.
  • smaU amounts of other anti-asthmatics and bronchodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophyUine and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • the compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration. A preferred range for inhaled administration is 10-99%, especiaUy 60-99%, for example 90, 95 or 99%.
  • Microfine powder formulations may suitably be administered in an aerosol as a metered dose or by means of a suitable breath-activated device.
  • Suitable metered dose aerosol formulations comprise conventional propeUants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulphate and density modifiers such as sodium chloride.
  • Suitable solutions for a nebulizer are isotonic sterilised solutions, optionally buffered, at for example between pH 4-7, containing up to 20mg/ml of compound but more generally 0.1 to lOmg/ml, for use with standard nebulisation equipment
  • a unit dose form of a composition of the invention may contain from 0.1 to lOOOmg of a compound of the invention (0.001 to lOmg via inhalation) and more usually from 1 to 500mg, for example 1 to 25 or 5 to 500mg.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from lmg to l for a 70 kg human adult and more particularly from 5 to 500mg. That is in the range of about 1.4 x 10 ⁇ 2 mg/kg/day to 14 mg/kg/day and more particularly in the range of about 7 x 10 * 2 mg/kg/day to 7 mg/kg day.
  • Procedure 1 The ability of test compounds to inhibit the release of soluble CD23 was investigated by use of the foUowing procedure.
  • RPMI 8866 Cell membrane CD23 cleavage activity assay Plasma membranes from RPMI 8866 cells, a human Epstein-Barr virus transformed B-cell line (Sarfati et al.. Immunology 60 [1987] 539-547) expressing high levels of CD23 are purified using an aqueous extraction method. Cells resuspended in homogenization buffer (20mM HEPES pH 7.4, 150 mM NaCl, 1.5 mM MgC12, 1 mM DTT) are broken by N2 cavitation in a Parr bomb and the plasma membrane fraction mixed with other membranes is recovered by centrifugation at 10,000Xg.
  • homogenization buffer (20mM HEPES pH 7.4, 150 mM NaCl, 1.5 mM MgC12, 1 mM DTT
  • the light peUet is resuspended in 0.2 M potassium phosphate, pH 7.2 using 2 ml per 1-3 g wet ceUs and the nuclear peUet is discarded.
  • the membranes are further fractionated by partitioning between Dextran 500 (6.4% w/w) and polyethylene glycol (PEG) 5000 (6.4% w/w) (ref), at 0.25 M sucrose in a total of 16 g per 10-15 mg membrane proteins [Morre and Morre, BioTechniques 7, 946-957 (1989)].
  • the phases are separated by brief centrifugation at lOOOXg and the PEG (upper) phase is collected, diluted 3-5 fold with 20 mM potassium phosphate buffer pH 7.4, and centrifuged at 10 ,000Xg to recover membranes in that phase.
  • the peUet is resuspended in phosphate-buffered saline and consists of 3-4 fold enriched plasma membranes as weU as some other ceU membranes (e.g. lysosomes, Golgi).
  • the membranes are a quoted and stored at -80°C. Fractionation at 6.6 % Dextran/PEG yields plasma membranes enriched 10-fold.
  • the fractionated membranes are incubated at 37°C for times up to 4 hrs to produce fragments of CD23 which are separated from the membrane by filtration in 0.2 micron Durapore filter plates (MiUipore) after quenching the assay with 5 uM Preparation 1 from P 30994.
  • sCD23 re ascd from the membrane is determined using the El A kit from The Binding Site (Birmingham, UK) or a similar one utilizing MHM6 anti-CD23 mAb [Rowe et al., Int J. Cancer, 29, 373-382 (1982)] or another anti-CD23 mAb as the capture antibody in a sandwich EIA..
  • the amount of soluble CD23 made by 0.5 ug membrane protein in a total volume of 50 ul phosphate- buffered saline is measured by EIA and compared to the amount made in the presence of various concentrations of inhibitors.
  • Inhibitors are prepared in solutions of water or dimethylsulfoxide (DMSO) and the final DMSO concentration is not more than 2 %.
  • IC50's are determined by curve fitting as the concentration where 50 % inhibition of production of sCD23 is observed relative to the difference in sCD23 between controls incubated without inhibitor.
  • Test compounds are dissolved in dimethylsulphoxide (DMSO) at a stock dilution of lO' ⁇ M dUuted 1 in 100 in TCM and then as above. The plates are incubated for 12 days at 37°C in a 95% air/5% CO2 humidified incubator. At the end of the culture period the supernatants were removed with the wells and centrifuged (200xg for 10 minutes) to remove any non-adherent cells. There was no toxicity as assessed by trypan blue dye exclusion. The IgE concentration in the supernatants was measured by ELISA.
  • DMSO dimethylsulphoxide
  • test compounds to inhibit the formation of human IgE in vitro was investigated using the following procedure: Human tonsiUar B lymphocytes were suspended in RPMI 1640 medium containing 10% foetal calf serum, 2mM glutamine, 50 micro M 2-mercaptoethanol and 50 micro g/ml gentamycin (TCM) at a concentration of 1.25 x 10 ⁇ cells/ml. 800 micro 1 of the cell suspension were aliquoted into the wells of a 48 well plate. 100 micro 1 of TCM or IL4 at lOOng/ml and antibody to CD40 at 10 microg/ml was added in quadriplicate to the appropriate wells, followed by
  • Test compounds are dissolved in DMSO at a stock dilution of 10"2M diluted 1 in 100 in TCM and then as above. The plates are incubated for 11 days at 37°C in a 95% air/5% CO2 humidified incubator. At the end of the culture period the supematents were removed from the we Us and centrifuged (200xg for 10 minutes) to remove any non-adherent cells. There was no toxicity as assessed by trypan dye exclusion. The IgE concentration in the supernatants was measured by ELISA.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Certains inhibiteurs de métalloprotéases matricielles telles que la collagénase peuvent inhiber la libération de la protéine CD23 humaine soluble et sont, par conséquent, utiles dans le traitement et la prophylaxie d'états dans lesquels un excès de CD23 soluble est impliqué, tels que l'allergie et les maladies auto-immunes.
EP97901056A 1996-01-17 1997-01-14 Utilisation medicale Withdrawn EP0909169A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9601042.6A GB9601042D0 (en) 1996-01-17 1996-01-17 Medical use
GB9601042 1996-01-17
PCT/EP1997/000197 WO1997025981A1 (fr) 1996-01-17 1997-01-14 Utilisation medicale

Publications (1)

Publication Number Publication Date
EP0909169A1 true EP0909169A1 (fr) 1999-04-21

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP97901056A Withdrawn EP0909169A1 (fr) 1996-01-17 1997-01-14 Utilisation medicale

Country Status (4)

Country Link
EP (1) EP0909169A1 (fr)
JP (1) JP2000503313A (fr)
GB (1) GB9601042D0 (fr)
WO (1) WO1997025981A1 (fr)

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
GB9929527D0 (en) * 1999-12-14 2000-02-09 Smithkline Beecham Plc Novel compounds

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Also Published As

Publication number Publication date
JP2000503313A (ja) 2000-03-21
WO1997025981A1 (fr) 1997-07-24
GB9601042D0 (en) 1996-03-20

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