EP0683674A1 - Utilisation d'inhibiteurs de la thrombine pour lutter contre des maladies neurodegeneratives - Google Patents

Utilisation d'inhibiteurs de la thrombine pour lutter contre des maladies neurodegeneratives

Info

Publication number
EP0683674A1
EP0683674A1 EP94906174A EP94906174A EP0683674A1 EP 0683674 A1 EP0683674 A1 EP 0683674A1 EP 94906174 A EP94906174 A EP 94906174A EP 94906174 A EP94906174 A EP 94906174A EP 0683674 A1 EP0683674 A1 EP 0683674A1
Authority
EP
European Patent Office
Prior art keywords
thrombin
inhibitors
neurodegenerative diseases
brain
rats
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Withdrawn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
EP94906174A
Other languages
German (de)
English (en)
Inventor
Thomas Friedrich
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Publication of EP0683674A1 publication Critical patent/EP0683674A1/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Withdrawn legal-status Critical Current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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • thrombin inhibitors to combat neurodegenerative diseases
  • the present invention relates to the use of thrombin inhibitors for the treatment of neurodegenerative diseases.
  • Thrombin inhibitors are important therapeutic substances which are used for the prophylaxis and treatment of coagulation disorders such as thrombosis or arterial reocclusions in the event of a heart attack and stroke (Talbot, MD and Butler, KD, Drug News and Perspectives, 3, 357-363 (1990) ) be used.
  • the central role of thrombin in these diseases has long been known (J.W. Fenton II, et al., Blood Coagulation and Fibrinolysis 2, 69-75 (1991)).
  • Coagulation is a process of proteases activating in a cascade manner, at the end of which is the conversion of prothrombin to thrombin.
  • Thrombin itself releases the fibrin from the fibrinogen molecule by splitting off peptides. Fibrin polymerizes into an insoluble network and closes wounds or - in the case of illness - a vital blood vessel.
  • Two substance classes can be distinguished from the numerous substances that attack thrombin: high-molecular substances such as peptides and proteins (MW> 1000 DA) and low-molecular substances.
  • the high molecular weight substances include substances that are described in patent applications WO92 / 01710; W091 / 19734 and WO91 / 02750 are described. These are thrombin inhibitors which consist of a peptide derived from the hirudin which recognizes the fibrinogen binding site of the thrombin. This functional part of the molecule is coupled via a peptide or non-peptide linker to a molecular part which occupies the protease pocket and which is of the D-PHE-PRO-ARG type.
  • Antithrombins from blood-sucking animals such as hirudin from the leech Hirudo Medicinalis (Markwardt, F., Hematology 7, 255-269, (1988)) or Hirulline from Hirudo Mallinensis (Electricwald, A. et al., Blood Coag.) Have even higher molecular weights Fibrin. 2, 83-89, (1991)).
  • hirudin from the leech Hirudo Medicinalis
  • Hirulline from Hirudo Mallinensis
  • the serine protease thrombin plays an important role in the brain outgrowth in order to pave the way for the growing neurites (Gurwitz, D. and Cunningham, DD; Proc. Natl. Acad. Sci. USA 85, 3440-3444 (1988 )).
  • Thrombin separates brain cells so that other brain cells can make connections.
  • many cell-cell connections are interrupted and neurodegenerative phenomena occur.
  • thrombin binds to the thrombin receptor and activates it by cutting in the amino acid sequence NATLDPR ⁇ SFLLRNPN between arginine and serine. Activation of the thrombin receptor triggers intracellular signal processes and thus causes a destructive effect on the cellular architecture (Hana S. et al., Neuron 1, 363-375 (1992)).
  • Patent application WO 92/11850 describes the use of calpain inhibitors for the treatment of neurodegenerative diseases.
  • the inhibitors described belong to the isocoumarin type. In addition to calpain, they also inhibit many other proteases and are therefore very unspecific.
  • the invention relates to the use of thrombin inhibitors for the production of medicaments for combating neurodegenerative diseases.
  • Thrombin inhibitors suitable for the invention are high molecular weight inhibitors such as hirudins, hirullins and their muteins, C-terminal hirudin fragments or modifications, protease Nexin I and thrombin inhibitors which consist of a C-terminal peptide of hirudin or its modification thereof in connection with a protease pocket binding D-PHE-PRO-ARG exist.
  • the two functional parts of the molecule are connected by peptide or non-peptide spacers (WO 92/01710; WO 91/10734; WO91 / 02750).
  • Thrombin inhibitors from blood-sucking animals such as ticks, bugs and other leeches are also suitable. These high molecular weight inhibitors generally do not penetrate the blood-brain barrier.
  • the blood-brain barrier can, however, be made permeable by osmotic shocks or the substances described are directly in z.
  • B. introduced the spinal fluid from where they reach the site of action.
  • thrombin inhibitors are low molecular weight compounds with a molecular weight below 1000DA.
  • thrombin inhibitors substituted guanidinoalkyl derivatives, amidinophenyl derivatives, guanidinophenyl derivatives, lysine derivatives, boronic acid and phosphonic acid derivatives of arginine and lysine.
  • the invention further relates to medicaments which contain thrombin inhibitors and a nerve growth factor. Such drugs are also suitable for combating neurodegenerative diseases.
  • a nerve growth factor is a protein that is important for the development and maintenance of the sympathetic nervous system and sensory nerves and other brain functions (Borsani, G. et al., Nucleic Acids Res., 18, 4020 (1990)). It stimulates division and differentiation of these cells.
  • Neurodegenerative diseases are diseases in which the neuronal organization of the brain is impaired
  • the thrombin inhibitors can be administered orally or parenterally, subcutaneously, intravenously, intramuscularly, transdermally, intra-sterically, intrathecally, as an infusion and directly into the brain or as a spray.
  • the dosage depends on the age, condition and weight of the patient and on the type of application.
  • the daily dose of active substance is between approximately 100 ⁇ g and 10 mg / kg body weight when administered orally and between approximately 10 ⁇ g and 10 mg / kg body weight when administered parenterally.
  • the new compounds can be used in the customary pharmaceutical application forms solid or liquid, for. B. in conventional galenic tablets, film-coated tablets, capsules, powders, granules, dragees or solutions. These are manufactured in the usual way.
  • the active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or
  • rats were operated on (unilateral lesion) or sham-operated and treated with thrombin inhibitors of various concentrations through a cannula implanted in the lateral ventricle. Training began in a "two-compartment step through passive avoidance" apparatus twenty days after the lesion. The rats were divided into different groups. Untreated rats were given contour solutions in which the thrombin inhibitor was replaced by serum albumin. Hirudin and protease Nexin-1 were used as thrombin inhibitors. The amounts ranged from 1 ⁇ g / kg to 100 ⁇ g / kg body weight. The latency of staying in an illuminated chamber after electroshock in an adjacent dark chamber is observed.
  • the rats were anesthetized and the brain fixed in situ. Sections were made from the brains obtained and subsequently fixed and cortical choline acetyltransferase positive neurons were detected with an avidin-biotin antibody system. sen. The staining neurons were evaluated as in Casamenti et al. described (Zeiss-Kontron IBASII).
  • thrombin inhibitor (hirudin and nexin-1) between 10-1000 ⁇ g / week.
  • a second experimental group received the thrombin inhibitor (hirudin, Nexin-1) in a concentration of 10-1000 ⁇ g / week together with 1-10 ⁇ g nerve growth factor.
  • Control rats receive the same filling (an artificial cerebrospinal fluid with rat serum albumin) with the one-time addition after 2 weeks, omitting the thrombin inhibitor (eg hirudin).
  • thrombin inhibitor eg hirudin
  • test 1 The rats were tested again after 1 to 2 (test 1) and 3 to 4 weeks (test 2) in the water tank.
  • test 2 the rats treated with thrombin inhibitor did not show any significant improvement in their behavior and their performance in comparison to the control rats.
  • the performance in the water tank was significantly better than that of the control rats and comparable to the performance of the unaffected rats. The improvement in performance is due to better preservation of the memories from the first test.
  • the second experimental group which had received the combination of thrombin inhibitor and nerve growth factor, showed significantly improved performances.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Neurosurgery (AREA)

Abstract

On utilise des inhibiteurs de la thrombine pour traiter des maladies neurodégénératives.
EP94906174A 1993-02-09 1994-01-29 Utilisation d'inhibiteurs de la thrombine pour lutter contre des maladies neurodegeneratives Withdrawn EP0683674A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4303646A DE4303646A1 (de) 1993-02-09 1993-02-09 Die Verwendung von Thrombininhibitoren zur Bekämpfung neurodegenerativer Erkrankungen
DE4303646 1993-02-09
PCT/EP1994/000259 WO1994017821A1 (fr) 1993-02-09 1994-01-29 Utilisation d'inhibiteurs de la thrombine pour lutter contre des maladies neurodegeneratives

Publications (1)

Publication Number Publication Date
EP0683674A1 true EP0683674A1 (fr) 1995-11-29

Family

ID=6479921

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94906174A Withdrawn EP0683674A1 (fr) 1993-02-09 1994-01-29 Utilisation d'inhibiteurs de la thrombine pour lutter contre des maladies neurodegeneratives

Country Status (5)

Country Link
EP (1) EP0683674A1 (fr)
JP (1) JPH08507047A (fr)
CA (1) CA2153420A1 (fr)
DE (1) DE4303646A1 (fr)
WO (1) WO1994017821A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999034789A1 (fr) * 1998-01-08 1999-07-15 Hoffman Keith B Utilisation d'inhibiteurs de serine protease pour inhiber la pathophysiologie et la neuropathologie chez un hote
DE19937656A1 (de) * 1999-08-13 2001-02-15 Aventis Behring Gmbh Verwendung von Antithrombin III zur Prophylaxe und Therapie von Erkrankungen

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196404B1 (en) * 1989-08-18 1996-09-10 Biogen Inc Inhibitors of thrombin
WO1991004014A1 (fr) * 1989-09-21 1991-04-04 Synergen, Inc. Procede de transport de compositions a travers la barriere hemato-encephalique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9417821A1 *

Also Published As

Publication number Publication date
JPH08507047A (ja) 1996-07-30
DE4303646A1 (de) 1994-08-11
CA2153420A1 (fr) 1994-08-18
WO1994017821A1 (fr) 1994-08-18

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