WO2001035967A1 - Inhibiteurs d'heparanase utilises dans le traitement de l'insuffisance cardiaque - Google Patents

Inhibiteurs d'heparanase utilises dans le traitement de l'insuffisance cardiaque Download PDF

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WO2001035967A1
WO2001035967A1 PCT/EP2000/011441 EP0011441W WO0135967A1 WO 2001035967 A1 WO2001035967 A1 WO 2001035967A1 EP 0011441 W EP0011441 W EP 0011441W WO 0135967 A1 WO0135967 A1 WO 0135967A1
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heparanase
treatment
heart failure
inhibitors
use according
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PCT/EP2000/011441
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German (de)
English (en)
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Dieter Herr
Alfred Hahn
Volker Laux
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Abbott Gmbh & Co. Kg
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Priority to EP00977548A priority Critical patent/EP1229921A1/fr
Priority to AU15221/01A priority patent/AU1522101A/en
Publication of WO2001035967A1 publication Critical patent/WO2001035967A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Heparanase inhibitors for the treatment of heart failure are highly paranase inhibitors for the treatment of heart failure.
  • the present invention relates to the use of at least one heparanase inhibitor for the treatment of heart failure and related signs, symptoms and / or malfunctions and methods for the production of pharmaceutical agents for the treatment of heart failure.
  • Proteoglycans are polyanionic substances of high molecular weight in which different types of heteropolysaccharide chains are covalently bound to a polypeptide backbone.
  • the polysaccharide groups of the proteoglycans formerly known as mucopolysaccharides, are now known as glycosaminoglycans.
  • a large number of enzymes are involved in the construction, conversion and degradation of these proteoglycans.
  • Proteolysis can release glycosaminoglycans, which in turn are broken down into smaller fragments under the action of glycosaminoglycan endoglycosidases, while corresponding exoglycosidases release monosaccharides from the non-reducing ends of the glycosaminoglycans.
  • Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPG) occur on the extracellular surface and in the extracellular matrix.
  • the HS chains are generally formed from clusters of sulfated disaccharide units, primarily 1-4 N-sulfated glucosamines bonded to ⁇ -iduronic acid residues, which pass through regions with little or no sulfate, primarily 1-4 at ⁇ -D -Glucuronic acid bound N-acetylated glucosamines, separated from each other. They are believed to play a major role in cell-cell and cell-matrix interactions that are involved in various physiological and pathophysiological processes. Examples include the adhesion, migration, differentiation and proliferation of cells.
  • HS and / or HSPG Various molecules are reported to interact with HS and / or HSPG. These are either growth factors (eg FGF, PDGF, VEGF), cytokines (IL-2), extracellular matrix proteins (fibronectin, collagen), factors involved in hemostasis (heparin factor II), or molecules of a different nature, e.g. lipoproteins, DNA topoisomerases and ⁇ -amyloid proteins (cf.Hileman et al. (1998) BioEssays 20, 156-167; Stringer and Gallagher (1997) Int. J. Biochem Cell Biol 29, 709-714 ; Rapraeger (1993) Curr. Opin Cell. Biol. 5, 844-853; Bernfield et al. (1993) Development 1993 Suppl.
  • growth factors eg FGF, PDGF, VEGF
  • IL-2 cytokines
  • extracellular matrix proteins fibronectin, collagen
  • factors involved in hemostasis heparin factor II
  • heparanase received attention because they were associated with the metastasis of tumors, inflammatory processes and leukocyte migration (WO 95/24907; US-A-5,817,800; US-A-5,262, 403; Vlodavsky et al . (1999) Genbank Accession No. AF 144325; Hulett et al. (1999) Nature Medicine 5,
  • heparanase was originally discovered in murine metastatic melanoma cells. Heparanase cleaves HS into characteristic high molecular weight fragments and this activity has been associated with the metastatic potential of melanoma cells.
  • the object of the present invention is to provide new therapeutic applications for modulating the heparanase activity.
  • the present invention relates to the use of at least one heparanase inhibitor for the treatment of heart failure.
  • cardiac insufficiency means an inability of the heart to provide the necessary support.
  • heart failure describes the state of a heart in which compensation mechanisms such as heart rate, contractility, stroke volume, hypertension are not sufficient to maintain a normal cardiac output. It is a weakness of the pump function.
  • Heart failure can affect the entire heart (global heart failure) or parts of it, for example left or right heart failure.
  • Preferred according to the invention is the treatment of myocardial insufficiency, i.e. Heart failure due to a change in the myocardium.
  • myocardial insufficiency i.e. Heart failure due to a change in the myocardium.
  • cardiomyopathies and preferably primary cardiomyopathies for example hypertrophic obstructive or non-obstructive cardiomyopathies characterized by hypertrophy of the heart, especially the chamber septum and left ventricle, and congestive cardiomyopathies characterized by hypertrophy and dilatation of the heart (also as dilated congestive cardiomyopathies).
  • the forms of heart failure, in particular congestive heart failure, which are preferably treated according to the invention are based on one or more of the changes in the myocardium listed below: hypertrophy of individual or all wall layers, decrease in muscle extensibility, heart enlargement, in particular enlargement of the ventricle, in particular without increasing the thickness of the ventricular muscles, decrease in the thickness of the ventricular muscles and fibrous changes in the ventricular muscles.
  • the indication heart failure to be treated according to the invention is generally characterized by a progressive development, ie the conditions described above change over time, the degree of severity generally increases and, if appropriate, conditions can merge with one another or other conditions can change to existing conditions draw near.
  • heart failures are treated which are preceded or accompanied by a lowering of the pH value of the affected heart parts.
  • Values in the acidic pH range usually around 2 to 6.5, around 3 to 6 and especially around 4.5 to 5.5 are important here.
  • the treatment of heart failure according to the invention or the conditions on which it is based enable a number of other signs, symptoms and / or malfunctions to be treated which are related to heart failure, i.e. especially accompany the disease states described above.
  • These include, for example, changes in the peripheral circulation, in particular congestion in the large and / or in the small circulation, e.g. Lung and liver congestion, a reduction in the blood supply to the peripheral circulation, respiratory disorders (dyspnea), kidney function, e.g. Nocturia, and the electrolyte, e.g. peripheral edema, breast and abdominal addiction, etc.
  • These signs, symptoms and / or malfunctions often form patterns or groups which are referred to as syndromes, so that, according to the invention, the treatment of the heart failure syndrome results.
  • Treatment in the sense of the invention includes not only the treatment of acute or chronic signs, symptoms and / or malfunctions, but also preventive treatment (prevention).
  • One purpose of acute or chronic treatment is to remedy the disorders, regulate the conditions, or alleviate the signs, symptoms and / or malfunctions.
  • the purpose of the treatment is to reduce the activity of the heparanase.
  • One purpose of preventive (preventive) treatment is to prevent the occurrence of the disorders, conditions, signs, symptoms and / or malfunctions, which includes a time delay in the occurrence.
  • Treatment can be symptomatic, for example as symptom suppression be aligned. It can be short-term, medium-term, or it can also be long-term treatment, for example in the context of maintenance therapy.
  • heparanase inhibitor describes substances which inhibit the enzymatic activity of heparanase or its expression.
  • inhibition is understood to mean a reduction in the enzyme activity, especially the activity as endogenous glycosidase, endoglucuronidase, ⁇ -glucuronidase and in particular endo- ⁇ -glucuronidase, or the expression of heparanase.
  • the enzyme activity of heparanase leads, for example, to the cleavage of glycosaminoglycans, optionally as part of proteoglycans, in particular heparan sulfate, or the corresponding proteoglycans.
  • Heparase inhibitors according to the invention preferably bring about a reduction in the HS and HSPG degradation by heparanase.
  • inhibitors of mammalian heparanase EC 3.2.1
  • human heparanase and especially the heparanase with the amino acid sequence SEQ ID NO: 2 encoded by the cDNA with SEQ ID NO: 1 are preferred.
  • Inhibitors according to the invention usually bind to heparanase or to nucleic acids encoding heparanase, e.g. DNA or mRNA. Binding is understood to mean any molecular interaction between inhibitor and enzyme or nucleic acid, in particular under physiological conditions. These are usually classic interactions, which include electrostatic forces, van der Waals forces, hydrogen bonds, hydrophobic bonds, or metal complex-like coordinative bonds. In addition to the reversible molecular interactions mentioned above, irreversible interactions between inhibitor and enzyme can also be considered, e.g. covalent bonds.
  • competitive enzyme inhibitors bind in the region of or one of the active domains of heparanase and compete with other substrates for their binding site (s) (competition).
  • competitive enzyme inhibitors are understood to mean those which compete with a comparison substrate, in the present case preferably heparan sulfate, for binding to heparanase, ie the binding of one hinders the binding of the other. Because of this binding to heparanase, competitive enzyme inhibitors can also be referred to as heparanase substrates.
  • inhibitors are preferably substrates which, in comparison to the natural substrate or substrates, are not or at least less accessible to the catalytic activity of heparanase, ie they are not or only comparatively accessible to a small extent by heparanase, in particular cleaved. It is also possible to use non-competitive inhibitors which, for example, bind essentially irreversibly to active domains or to the heparanase elsewhere and, for example via allosteric effects, have an influence on the enzyme activity.
  • the principle applies that the displacement of a substrate by an inhibitor increases with decreasing binding affinity of the substrate or increasing binding affinity of the inhibitor. It is therefore expedient for inhibitors which can be used according to the invention to have a high binding affinity for heparanase. Such a favorable binding affinity allows an effective displacement of naturally occurring enzyme substrates, for example heparan sulfates and heparan sulfate proteoglycans, the concentration of inhibitor required for binding a certain amount of this inhibitor to the enzyme or for displacing a certain amount of a substrate with increasing Binding affinity of the inhibitor decreases.
  • inhibitors are therefore preferred whose binding affinity is so great that they can be administered as an active ingredient in an effective medical treatment in acceptable amounts.
  • Inhibitors according to the invention are therefore preferably administered in daily doses of approximately 0.01 to 30 mg / kg body weight and in particular approximately 0.1 to 15 mg / kg body weight.
  • the competitive inhibition of the binding of heparanase inhibitors can also be evaluated to the extent that inhibitors preferred according to the invention have half-maximum inhibitory constants IC 50 in vitro of less than 10 -3 M, preferably less than 10 -4 M and in particular less than 10 -5 M and with non-competitive inhibition of less than 10 -4 M, preferably less than 10 -5 M and in particular less than 10 ⁇ 6 M.
  • the expression inhibitors are, in particular, oligonucleotides which act, for example, in the sense of an antisense RNA or DNA, or in the sense of the triple helix technique.
  • heparanase inhibitors are glycosaminoglycans with structural similarity to the natural substrates of heparanase, in particular heparan sulfates. These include heparins, heparin fracture Nen and heparin fragments, for example heparins of a certain molecular weight, heparin derivatives, for example heparins with at least partially reduced carboxyl groups, at least partially N-desulfated, N-acetylated heparins, for example in EP 0 254 067 A2, WO 92/01003 and US Pat. No.
  • N-desulfated, N-acetylated heparin described at least partially N, 0-desulfated, N-resulfated heparins, for example the compounds described in WO 92/01003 and US Pat. No. 5, 206,223, and O-acylated heparins, for example those in the compounds described in EP 0 356 275 AI.
  • Heparin is preferably obtained from natural sources, for example the intestinal mucosa of cattle or pigs. Fragmentation and / or fractionation can be carried out in the usual way.
  • Carboxyl groups can be reduced with NaBH, for example.
  • Sulfate groups can be removed, for example, by treatment with water- or methanol-containing DMSO, the degree of desulfation depending on the reaction time, the reaction temperature and the addition of water or methanol.
  • N-acetylation can be accomplished, for example, with acetic anhydride under alkaline conditions and the resulfation can be accomplished, for example, with a triethylamine-sulfur trioxide complex.
  • glycosaminoglycans can also be derivatized, for example hyaluronic acid, chondroitin-4-sulfate, chondroitin-6-sulfate, tertiary sulfate, keratin sulfate and heparan sulfate and their proteoglycans, as described using the example of O-acylation in EP 0 356 275 Al is.
  • sulfated oligosaccharides for example those described in WO 96/33726, ie in particular sulfated mannopentaose phosphates, maltohexaose sulfates and the like, and sulfated polysaccharides, for example those described in WO 88/05301, that is to say in particular heparin, fucoidan, pentosan sulfate, dextran sulfate and carrageenan -Lambda.
  • the oligosaccharides and polysaccharides containing phosphosugars mentioned in WO 90/01938 can also be used.
  • Glycomimetic saccharopeptides for example those of the formula described in WO 96/35700, are also suitable
  • radicals W independently of one another for fucose
  • 3-amino-3-deoxyglucose 4-amino-4-deoxyglucose, glucose, galactose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, glucosaminuronic acid, neuraminic acid, maltose, maltotriose, iduronic acid, 2,5-anhydromannitol, mannose, mannuronic acid, and cellobiose stand;
  • radicals Y independently of one another represent -NR 3 -C (0) - and -C (0) -NR 3 -;
  • radicals X independently of one another represent a difunctional or polyfunctional group, in particular ethylene glycol, ethylene glycol oligomers, lower alkyl, optionally substituted alkyl, amino acids and peptides;
  • R 3 represents -H, alkyl of 1 to 8 carbon atoms and aralkyl of 5 to 8 carbon atoms.
  • Laminarin sulfates also called laminaran sulfates, are linear polymers made from ⁇ -1,3-linked glucose residues with possibly small proportions of ⁇ - (1,6) linkages and 2 to 3% D-mannitol end groups, in particular the sodium salt with a molar ratio of at least 1: 1 sulfate groups to monosaccharide units can also be used as a heparanase inhibitor (cf. WO 95/24907).
  • heparanase inhibitors are suramin and trachyspinic acid.
  • Y stands for -COOH, -P0 3 H 2 -P (0) (OR 6 ) (OH), -P (0) R 6 (OH), tetrazole and -S0 3 H, in which
  • X represents NH, 0 or S
  • R represents a hydrogen atom or -C (0) NHC 6 (R 7 ) 5 , in which C ⁇ (R 7 ) 5 preferably represents optionally mono- to pentasubstituted phenyl and the substituents R 7 are selected from OH, halogen, -COOH , -P0 3 H 2 or -S0 3 H.
  • the salts of these compounds are also included.
  • Illustrative examples of these compounds are (Z) -O- (D-glucopyranuronosylidene) amino-N-phenylcarbamate and (5R, Z) -0- (5-C-phosphonato-D-xylopyranosylidene) amino-N-phenylcarbamate and their sodium salts.
  • These compounds can be prepared in a manner known per se, for example using the processes described in EP 0 642 799.
  • Low molecular weight heparanase inhibitors mostly synthetic compounds, can be used advantageously in many ways.
  • Aptamers which are nucleic acids, usually oligonucleotides, with sufficient affinity for heparanase, can also be used as inhibitors.
  • Heparanase-specific antibodies can also be useful as heparanase inhibitors. It can be polyclonal antisera, monoclonal antibodies, antibody fragments such as F (ab), Fc, etc., chimeric, humanized and recombinant antibodies. Such antibodies can be produced in a manner known per se. Heparanase as such or antigenic fragments thereof, which as a rule are coupled to customary carrier proteins, can be used as the immunogen.
  • Example 8 of WO 99/43830 describes, for example, the production of a polyclonal antiserum against selected peptides of human heparanase.
  • WO 95/04158 describes the production of selected heparinase peptides, in particular a C-terminal sequence, there called SEQ ID NO: 42, and the production of antisera directed against them and their usefulness as heparanase inhibitors.
  • WO 96/08559 describes phosphorothioate or phosphorodithioate antisense oligonucleotides with preferably 7 to 30 nucleotides, which are essentially formed from dG and / or dT nucleotides. Specifically, are suitable for the inhibition of endoglycosidases, in particular heparanases, for example the oligonucleotides of the sequences SEQ ID NO: 2,4,6,10 described there.
  • the application according to the invention is not limited to the inhibitors mentioned above. Rather, any substance in the presence of which the heparanase activity is lower than in the absence thereof can be used according to the invention as a heparanase inhibitor.
  • Test systems are known for measuring the heparanase activity. These are generally based on the use of labeled heparan sulfates or heparan sulfate proteoglycans as a substrate, the conversion, ie the cleavage of this substrate and the associated release of certain fragments, being able to be followed on the basis of the label.
  • the substrates can be obtained biologically, for example by cultivating endothelial cells in radiolabeled 35 SO 4 or injecting radiolabelled sulfate into tumorous experimental animals, and recovering appropriately labeled heparan sulfate proteoglycans from the endothelial or tumor cells.
  • the substrates can also be synthesized chemically, for example by first partially deacetylating heparan sulfate and then reacetylating. By reductive amination of the free ends of heparan sulfate and subsequent addition of suitable labels, for example, fluorescence-labeled heparan sulfates can be produced.
  • the coupling chemistry customary in this area can be used, for example first aminating the reducing ends and then coupling glycosaminoglycans modified in this way to suitable matrices, for example agarose, sepharose and the like.
  • suitable matrices for example agarose, sepharose and the like.
  • Heparan sulfate proteoglycans or heparan sulfate peptides thereof can be coupled, for example, to CNBr-activated Sepharose.
  • Another possibility is to separate the degradation products by gel filtration, precipitation reactions, for example as described in Example J of WO 96/35700, and the like.
  • Fluorescence labels can advantageously be detected by means of HPLC, preferably exclusion HPLC.
  • HPLC preferably exclusion HPLC.
  • HS-binding proteins for example histidine-rich glycoproteins, Use wisely in immobilized form in order to separate non-degraded or only partially degraded heparanase substrate from degraded substrate and thereby enable its detection.
  • the heparanase used in these tests can be of natural or recombinant origin, so heparanase can be purified from a large number of tissues and body fluids, including serum.
  • the expression of human heparanase can be accomplished with the expression systems mentioned in WO 95/04158 and WO 99/43830.
  • the present invention therefore also relates to a method for identifying heparanase inhibitors, the activity of heparanase being determined in the presence and in the absence of at least one test substance.
  • test systems described above and other similarly suitable test systems can form the basis for in vitro screening methods, preferably for primary screening, with which one can read out from a large number of different substances those which are useful with regard to the use according to the invention
  • the present invention thus also relates to corresponding methods for identifying active substances for the treatment of heart failure and, based on this, the production of pharmaceutical agents for the treatment of heart failure.
  • Such a process for the development of active substances for the treatment of heart failure is characterized in that heparanase inhibitors are first selected from a large number of substances and used to produce the agent. For example, using combinatorial chemistry, extensive substance banks can be created that include myriads of potential active substances.
  • the screening of combinatorial substance libraries for substances with the desired activity can be automated. Screening robots are used for the efficient evaluation of the individual assays, which are preferably arranged on microtiter plates.
  • Kits and components for performing this assay can be obtained commercially, for example from Amersham Pharmacia Biotech.
  • solubilized or membrane-bound substrates are immobilized on small fluomicrospheres containing scintillation substance.
  • the substrate is radioactively marked and the scintillation substance is stimulated to emit light as long as the spatial proximity between scintillation Substance and radiolabeling is given, or the radioactive label is inserted into the immobilized substrate by the enzyme activity to be measured and, as a result, the scintillation substance is excited to emit light.
  • FlashPlate® technology known in the field of active substance screening. Kits and components for carrying out this assay can be obtained commercially, for example from NEN ® Life Science Products. This principle is also based on microtiter plates (96 or 384), which are coated with scintillation substance.
  • heparanase inhibitors includes a method as part of the treatment.
  • An effective amount of one or more heparanase inhibitors is administered to the individual to be treated, preferably a mammal, in particular a human, useful or domestic animal.
  • the treatment is carried out by adding it once or several times a day, optionally together or alternating with other active substances or preparations containing the active substance. Whether such treatment is indicated and in what form it must be carried out depends on the individual case and is subject to a medical assessment (diagnosis) to develop the existing signs, symptoms and / or malfunctions, risks, certain signs, symptoms and / or malfunctions , and other factors.
  • the teaching according to the invention is primarily aimed at the production of pharmaceutical agents for the treatment of an individual, preferably a mammal, in particular a human, useful or domestic animal.
  • the inhibitors are usually administered in the form of pharmaceutical compositions which comprise a pharmaceutically acceptable excipient with at least one inhibitor according to the invention, optionally also a mixture of several inhibitors according to the invention, and optionally further active ingredients.
  • These compositions can be administered, for example, by the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes.
  • suitable pharmaceutical formulations are solid pharmaceutical forms, such as powders, powders, granules, tablets, lozenges, sachets, cachets, coated tablets, capsules such as hard and soft gelatin capsules, suppositories or vaginal pharmaceutical forms, semi-solid medicinal forms.
  • neiforms such as ointments, creams, hydrogels, pastes or plasters
  • liquid pharmaceutical forms such as solutions, emulsions, in particular oil-in-water emulsions, suspensions, for example lotions, injection and infusion preparations, eye and ear drops.
  • Implanted delivery devices can also be used for the administration of inhibitors according to the invention. Liposomes, microspheres or polymer matrices can also be used.
  • inhibitors according to the invention are usually mixed or diluted with an excipient.
  • Excipients can be solid, semi-solid or liquid materials that serve as vehicles, carriers or media for the active ingredient.
  • Suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations can be pharmaceutically acceptable carriers or customary auxiliaries, such as lubricants, for example talc, magnesium stearate and mineral oil; Wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; Antioxidants; Antiirritatives; chelating agents; coating aids; Emulsion stabilizers; film formers; gelling agents; Odor masking agents; masking flavors; resins; Hydrocolloids; Solvents; Solubilizing agents; Neutralizing agents; Permeation accelerator; pigments; quaternary ammonium compounds; Refatting and overfatting agents; Ointment, cream or oil base materials; Silicone derivatives; spreading aids; stabilizers; Sterilanzien; Fundamentals of the suppository; Tablet excipients such as binders, fillers, lubricants, disintegrants or coatings; Propellant; Desiccant; Opacifiers; Thickener; waxes; plasticizer
  • a design in this regard is based on expert knowledge, as is shown, for example, in Fiedler, H.P., Lexicon of auxiliaries for pharmacy, cosmetics and related areas, 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.
  • FIG. 1 shows the gel electrophoretic separation of the amplificates obtained after RT-PCR according to Example 1 in parallel with molecular weight standards (MWM) and the negative control (negative).
  • MLM molecular weight standards
  • the animal model used was by Wiesener et al. in Circulation 95, 1253-1259 (1997).
  • Five rats treated with the aortic clamp technique (No. 3, 15, 24, 25, 112) developed congestive heart failure (cardiac hypertrophy).
  • the hearts were removed and the mRNA was isolated in the usual way.
  • the amount of heparanase mRNA expressed could be determined by RT-PCR by using the oligonucleotide with the sequence SEQ ID NO: 3 as sense primer and the oligonucleotide with the sequence SEQ ID NO: 4 as antisense primer.
  • the GADPH expression was measured as a housekeeping gene.
  • the same study was carried out on control animals (rats No. 11, 17, 19, 32, 33).
  • the respective amplificates obtained by RT-PCR were separated electrophoretically and their amount was quantified.
  • 1 shows the amplicons obtained after electrophoretic separation for animals 11, 17, 19, 32 and 33 of the control group and animals 3, 15, 24, 25 and 112 of the test group.
  • the quantification gave the following heparanase mRNA levels, each based on GAPDH expression:
  • the mean values are 4.289 ⁇ 0.75 for the control group and 4.153 ⁇ 0.06 for the test group. These values show that the pathological state induced in the model is not associated with regulation of the expression of heparanase mRNA, but 5 the intra- and extracellular acidification occurring in connection with cardiac hypertrophy and heart failure modulates the heparanase activity (Schini-Kerth et al (1997) Circulation 96, 3888-3896; Shrode et al. (1997) J Bioenerg Biomembr 29, 393-399; Kraus and Wolf (1996) Tumor Biol 17, 133-154; Tamagaki et al.

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Abstract

La présente invention concerne l'utilisation d'inhibiteurs d'héparanase dans le traitement de l'insuffisance cardiaque, notamment de l'insuffisance cardiaque congestive, et des indications, des symptômes et/ou des fonctions défectueuses connexes, tels que les oedèmes périphériques, la congestion des poumons et du foie, la dyspnée et l'hydropisie de la poitrine et du ventre. La présente invention concerne également un procédé de production d'agents pharmaceutiques permettant de traiter l'insuffisance cardiaque.
PCT/EP2000/011441 1999-11-19 2000-11-17 Inhibiteurs d'heparanase utilises dans le traitement de l'insuffisance cardiaque WO2001035967A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP00977548A EP1229921A1 (fr) 1999-11-19 2000-11-17 Inhibiteurs d'heparanase utilises dans le traitement de l'insuffisance cardiaque
AU15221/01A AU1522101A (en) 1999-11-19 2000-11-17 Heparanase inhibitors for the treatment of heart failure

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DE19955803.5 1999-11-19
DE19955803A DE19955803A1 (de) 1999-11-19 1999-11-19 Verwendung von Heparanase-Inhibitoren zur Behandlung von Hersinsuffizienz

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EP1417304A2 (fr) * 2001-07-13 2004-05-12 Imclone Systems, Inc. Methode et composition permettant d'inhiber l'activite de l'heparanase
US7326727B2 (en) 2002-08-05 2008-02-05 Oxford Glycosciences (Uk) Ltd. Furanthiazole derivatives as heparanase inhibitors
EP2343077A1 (fr) 2001-09-12 2011-07-13 SIGMA-TAU Research Switzerland S.A. Inhibiteurs d'heparanase à base de dérivés de glycosaminoglycanes totalement N-desulfates capables d'activité anti-angiogène et dépourvu d'effet anticoagulant

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DE10258770B4 (de) * 2001-12-18 2005-02-10 F. Hoffmann-La Roche Ag Verfahren zum Testen eines Mittels auf dessen Fähigkeit, die Heparanaseaktivität zu hemmen
CH696701A5 (de) 2001-12-18 2007-10-15 Hoffmann La Roche Verfahren zum Testen eines Mittels auf dessen Fähigkeit, die Heparanaseaktivität zu hemmen.
EP1479764A1 (fr) 2003-05-19 2004-11-24 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Peptides derives de Heparanas pour la vaccination des patients cancereux

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WO1996008559A1 (fr) * 1994-09-16 1996-03-21 Cardiac Crc Nominees Pty. Ltd. Inhibition de l'enzyme degradant la glycosaminoglycane et therapies contre les affections provoquees par cette enzyme
WO1999023214A1 (fr) * 1997-10-30 1999-05-14 The Trustees Of The University Of Pennsylvania Compositions et procedes permettant d'ameliorer la contractilite cardiaque induite par les purinocepteurs du myocyte p2 et modeles de ces derniers
WO1999043830A2 (fr) * 1998-02-24 1999-09-02 Pharmacia & Upjohn Company Polypeptides d'heparanase des plaquettes humaines, molecules polynucleotidiques les codant et procedes d'identification de composes modifiant l'activite de l'heparanase

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WO1996008559A1 (fr) * 1994-09-16 1996-03-21 Cardiac Crc Nominees Pty. Ltd. Inhibition de l'enzyme degradant la glycosaminoglycane et therapies contre les affections provoquees par cette enzyme
WO1999023214A1 (fr) * 1997-10-30 1999-05-14 The Trustees Of The University Of Pennsylvania Compositions et procedes permettant d'ameliorer la contractilite cardiaque induite par les purinocepteurs du myocyte p2 et modeles de ces derniers
WO1999043830A2 (fr) * 1998-02-24 1999-09-02 Pharmacia & Upjohn Company Polypeptides d'heparanase des plaquettes humaines, molecules polynucleotidiques les codant et procedes d'identification de composes modifiant l'activite de l'heparanase

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1417304A2 (fr) * 2001-07-13 2004-05-12 Imclone Systems, Inc. Methode et composition permettant d'inhiber l'activite de l'heparanase
EP1417304A4 (fr) * 2001-07-13 2005-11-23 Imclone Systems Inc Methode et composition permettant d'inhiber l'activite de l'heparanase
EP2343077A1 (fr) 2001-09-12 2011-07-13 SIGMA-TAU Research Switzerland S.A. Inhibiteurs d'heparanase à base de dérivés de glycosaminoglycanes totalement N-desulfates capables d'activité anti-angiogène et dépourvu d'effet anticoagulant
US7326727B2 (en) 2002-08-05 2008-02-05 Oxford Glycosciences (Uk) Ltd. Furanthiazole derivatives as heparanase inhibitors

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EP1229921A1 (fr) 2002-08-14
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