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WO2004016269A1 - Utilisation de vinca alcaloides, de taxane, de cryptophycine, d'epothilone ou d'eleutherobine pour le traitement de la maladie d'alzheimer - Google Patents

Utilisation de vinca alcaloides, de taxane, de cryptophycine, d'epothilone ou d'eleutherobine pour le traitement de la maladie d'alzheimer Download PDF

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Publication number
WO2004016269A1
WO2004016269A1 PCT/GB2003/003601 GB0303601W WO2004016269A1 WO 2004016269 A1 WO2004016269 A1 WO 2004016269A1 GB 0303601 W GB0303601 W GB 0303601W WO 2004016269 A1 WO2004016269 A1 WO 2004016269A1
Authority
WO
WIPO (PCT)
Prior art keywords
medicament
trk
alzheimer
disease
peptide
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.)
Ceased
Application number
PCT/GB2003/003601
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English (en)
Inventor
Peter A. Passmore
Stephen P. Mcilroy
Lawrence R. Mcgrath
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.)
Queens University of Belfast
Original Assignee
Queens University of Belfast
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
Priority claimed from GB0219241A external-priority patent/GB0219241D0/en
Priority claimed from GBGB0225206.2A external-priority patent/GB0225206D0/en
Application filed by Queens University of Belfast filed Critical Queens University of Belfast
Priority to AU2003260723A priority Critical patent/AU2003260723A1/en
Publication of WO2004016269A1 publication Critical patent/WO2004016269A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol

Definitions

  • the present invention relates to medicaments that are useful in the prevention, halting or reversal of Alzheimer's Disease progression in mammals and these medicaments are cytoskeletal and/or microtubule stabilisers.
  • AD Alzheimer's Disease
  • ⁇ -amyloid ⁇ -amyloid
  • APP Alzheimer Precursor Protein
  • ⁇ secretase (Vassar et al Science, 1999 Oct. 286 (5440) : 735- 41) , cleaves the last 100 amino acid residue of the APP C-terminus and this is further cleaved by the ⁇ secretase to produce the A ⁇ peptide.
  • the ⁇ secretase activity is known to be rate limiting step in this process.
  • the ⁇ secretase is not characterised fully but the presenilin family of proteins are known to be involved (Vassar R, J. Mol Neuroscience. 2001 Oct , 17 (2) : 157-70) .
  • an object of the present invention is to stabilise the microtubular network in cells using known and/or new cytoskeletal stabilising compounds, so that the actions and effects of A ⁇ can be overcome.
  • Some currently used anti-cancer drugs work by stabilising microtubules in cells, thereby lethally preventing mitosis, and we intend to show their ability to prevent, halt or reverse the biological activity of the A ⁇ peptide. Therefore, it is an object of the present invention to provide a medicament to prevent, limit or halt the progression of Alzheimer's Disease.
  • a medicament to prevent, limit or halt the progression of Alzheimer's Disease in patients including at least one cytoskeletal- stabilising agent.
  • Cytoskeletal components of the cell are deemed to include actin filaments, microtubules and intermediate filaments.
  • the cytoskeletal agent is at least one microtubule stabilising agent.
  • the cytoskeletal agent is at least one actin stabilising agent.
  • the medicament is a combination of at least one cytoskeletal stabilising agent and/or at least one microtubule stabilising agent.
  • the medicament includes a Vinca alkaloid, a taxane, a cryptophycine, epothilone or an eleutherobine .
  • the medicament is an inhibitor of microtubule destablisers .
  • the invention thus provides the use of any of these agents in the preparation of a medicament for the treatment of Alzheimer's Disease.
  • the medicament is or includes TaxolTM.
  • the medicament inhibits abnormal degradation of the Amyloid Precursor Protein and inhibits intra cellular build up of the A ⁇ peptide.
  • Abnormal degradation of APP includes degradation of APP according to the amyloid pathway as opposed to the neutrophic pathway.
  • the medicament is specifically targeted to the brain. To target the medicament to the brain the medicament preferably is able to cross the blood brain barrier.
  • a medicament including Trk A, or an analogue thereof including a family member Trk B or Trk C.
  • Trk A or an analogue thereof including a family member Trk B or Trk C in the preparation of a medicament for the treatment of Alzheimer's disease.
  • An agent includes a small molecule, compound, protein or part thereof.
  • FIG. 1 is a diagrammatic representation of the Amyloid Precursor Protein (APP) ;
  • Figure 2 is a diagrammatic representation of the APP protein of Figure 1, bound to kinesin, via the kinesin light chain, showing kinesin "walking" along a microtubule by selective binding of the kinesin heavy chain to ⁇ tubulin submits of the microtubule;
  • Figure 3 is a Western Blot showing decreased levels of kinesin light chain C (60-70 kDa) in the presence of increasing expression levels of the A ⁇ peptide;
  • Figure 5a is a Western Blot showing decreased levels of ⁇ tubulin (55kDa) and increasing levels of Amyloid ⁇ (4kDa) in the presence of increasing expression levels of the A ⁇ peptide;
  • Figure 5b is a diagrammatic representation of the Western Blot of figure 5a showing decreased levels of ⁇ tubulin (55kDa) and increasing levels of Amyloid ⁇ (4kDa) in the presence of increasing expression levels of the A ⁇ peptide;
  • FIG. 6 is a diagrammatic representation of the Western Blot showing decreasing levels of TrkA (140kDa) in the presence of increasing expression levels of the A ⁇ peptide
  • Figure 7 is a Western Blot showing increased levels of PHF - Tau in response to increased expression levels of A ⁇ peptide.
  • Figure 8 is a Western Blot showing decreased levels of TRK A in response to a mutation of PS2.
  • Amyloid Precursor Protein is a transmembrane protein that undergoes endoproteolysis by three proteases called ⁇ , ⁇ and ⁇ - secretase. After complete processing of the APP protein, the ⁇ -amyloid 42 amino acid peptide is released intracellularly.
  • Figure 2 is a diagrammatic representation of APP binding to the kinesin light chain of the molecular motor kinesin. Kinesin "walks" selectively along a microtubule by binding selectively to ⁇ -tubulin via its kinesin heavy chain subunit .
  • Figure 3 is a picture of a representative Western Blot for kinesin light chain of protein extracts from cells expressing no A ⁇ peptide (lane 1) ; constitutively low expression of A ⁇ peptide cells (lane 2) and constitutively high expression of A ⁇ peptide cells (lane 3), i.e. transfected with the vector constitutively encoding the C100 peptide; wherein down regulation of kinesin light chain is obvious in lane 3.
  • Figure 4 is a drawing of a representative Western Blot for kinesin light chain of protein extracts from cells expressing no A ⁇ peptide (lane 1) ; constitutively low expression of A ⁇ peptide cells (lane 2) and constitutively high expression of A ⁇ peptide cells (lane 3), i.e. transfected with the vector constitutively encoding the C100 peptide; wherein down regulation of kinesin light chain is obvious in lane 3.
  • Figure 5b is another Western Blot for ⁇ -tubulin of the same cells as shown in Figure 4b where it is clear that the ⁇ -tubulin concentration decreases while amyloid ⁇ protein increases accordingly. Furthermore, as shown in figure 6, levels of a nerve growth factor receptor Trk A, carried by vesicles that use APP to connect to a molecular motor, are also decreased in a A ⁇ peptide concentration dependent manner.
  • Trk A nerve growth factor receptor
  • Trk A is decreased when a PS2 mutation is introduced in a cell line.
  • the level of Trk A is also found to be decreased in cell lines having a PSl mutation or a mutation in APP leading to an increase in the A ⁇ expression.
  • Trk A is a receptor which upon ligand binding is internalised and translocates from the cellular membrane to the nucleus of the cell. The presence of Trk A in the nucleus causes the cell to continue to survive whereas a lack of Trk A in the nucleus promotes cell degradation. Trk A relies on cytoskeletal proteins for transport and thus disruption of the cytoskeletal proteins, as set out above, would decrease the level of Trk A being moved to the nucleus . As the movement of Trk A to the nucleus would be limited by disruption of cytoskeletal proteins, it is proposed to provide Trk A, family members Trk B or Trk C or an analogue thereof to the nucleus to promote cellular survival.
  • Figure 7 shows clearly increased levels of PHF-Tau due to the increasing levels of the A ⁇ peptide intracellularly.
  • Components of the cell that bind to the A ⁇ peptide more specifically will be investigated using standard methods, including specific chemical cross linking of the C100 and/or A ⁇ peptide in the living cell or using cell free systems.
  • the aim of the above experiments is to elucidate the complete mechanism of action of the C100 and A ⁇ peptides, so that the counter active activity of tubulin stabilising compounds like TaxolTM can be analysed.
  • the constitutively expressed C100 peptide vector does not allow for the regulation or switching on and off of the expression of the C100 peptide described above.
  • microtubule destabilisers proteins The effect of microtubule destabilisers in an essential part of further investigation.
  • Various modifications can be made without departing from the scope of the invention, for example, ways of negating the effect of microtubule destabilisers would elicit the same effect as medicaments to stabilise cytoskeletal proteins. Suitable inhibitors of microtubule destabilisers would be known to those in the art .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des médicaments utiles pour prévenir, arrêter ou inverser la progression de la maladie d'Alzheimer par stabilisation d'au moins un composé de stabilisation du cytosquelette et/ou des microtubules.
PCT/GB2003/003601 2002-08-17 2003-08-18 Utilisation de vinca alcaloides, de taxane, de cryptophycine, d'epothilone ou d'eleutherobine pour le traitement de la maladie d'alzheimer Ceased WO2004016269A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003260723A AU2003260723A1 (en) 2002-08-17 2003-08-18 Use of vinca alkaloyds, taxane, cryptophycine, ephitoline or eleutherobine for treating alzheimer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB0219241.7 2002-08-17
GB0219241A GB0219241D0 (en) 2002-08-17 2002-08-17 Medicaments
GBGB0225206.2A GB0225206D0 (en) 2002-10-30 2002-10-30 Medicaments
GBGB0225206.2 2002-10-30

Publications (1)

Publication Number Publication Date
WO2004016269A1 true WO2004016269A1 (fr) 2004-02-26

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PCT/GB2003/003601 Ceased WO2004016269A1 (fr) 2002-08-17 2003-08-18 Utilisation de vinca alcaloides, de taxane, de cryptophycine, d'epothilone ou d'eleutherobine pour le traitement de la maladie d'alzheimer

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AU (1) AU2003260723A1 (fr)
WO (1) WO2004016269A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6972335B2 (en) 1996-12-03 2005-12-06 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7759374B2 (en) 2002-08-23 2010-07-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US8673949B2 (en) 2008-04-24 2014-03-18 Bristol-Myers Squibb Company Use of epothilone D in treating Tau-associated diseases including Alzheimer's disease

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0870510A2 (fr) * 1997-04-11 1998-10-14 Eli Lilly And Company Combinaison synergique comprenant des dérivés de cryptophycine et des agents microtubules synergisants

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0870510A2 (fr) * 1997-04-11 1998-10-14 Eli Lilly And Company Combinaison synergique comprenant des dérivés de cryptophycine et des agents microtubules synergisants

Non-Patent Citations (10)

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Title
ADLARD PAUL A ET AL: "The effects of taxol on the central nervous system response to physical injury", ACTA NEUROPATHOLOGICA, vol. 100, no. 2, August 2000 (2000-08-01), pages 183 - 188, XP001173124, ISSN: 0001-6322 *
BOISSIÈRE F ET AL: "Trk neurotrophin receptors in cholinergic neurons of patients with Alzheimer's disease.", DEMENTIA AND GERIATRIC COGNITIVE DISORDERS. SWITZERLAND 1997 JAN-FEB, vol. 8, no. 1, January 1997 (1997-01-01), pages 1 - 8, XP008024311, ISSN: 1420-8008 *
CINEL B ET AL: "Solid-state and solution conformations of eleutherobin obtained from X-ray diffraction analysis and solution NOE data", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 41, no. 16, April 2000 (2000-04-01), pages 2811 - 2815, XP004195677, ISSN: 0040-4039 *
FURUKAWA K ET AL: "A microtubule stabilizing compound, taxol, attenuates neuronal vulnerability of tau mutations in FTDP-17", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 27, no. 1, 2001, 31st Annual Meeting of the Society for Neuroscience;San Diego, California, USA; November 10-15, 2001, pages 922, XP001173123, ISSN: 0190-5295 *
GIANNAKAKOU PARASKEVI ET AL: "A common pharmacophore for epothilone and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 97, no. 6, 14 March 2000 (2000-03-14), pages 2904 - 2909, XP002189845, ISSN: 0027-8424 *
KIDD P M: "A review of nutrients and botanicals in the integrative management of cognitive dysfunction.", ALTERNATIVE MEDICINE REVIEW: A JOURNAL OF CLINICAL THERAPEUTIC. UNITED STATES JUN 1999, vol. 4, no. 3, June 1999 (1999-06-01), pages 144 - 161, XP008024312, ISSN: 1089-5159 *
LEMAIRE LAURENT ET AL: "Magnetic resonance imaging of the neuroprotective effect of Xaliproden in rats", INVESTIGATIVE RADIOLOGY, vol. 37, no. 6, June 2002 (2002-06-01), pages 321 - 327, XP008024309, ISSN: 0020-9996 *
LI G ET AL: "STABILZATION OF THE CYCLIN - DEPENDENT KINASE 5 ACTIVATOR, P35, BY PACLITAXEL DECREASES BETA - AMYLOID TOXICITY IN CORTICAL NEURONS.", SOCIETY FOR NEUROSCIENCE ABSTRACT VIEWER AND ITINERARY PLANNER, vol. 2002, 2002, 32nd Annual Meeting of the Society for Neuroscience;Orlando, Florida, USA; November 02-07, 2002, pages Abstract No. 591.9, XP001172845 *
POLLACK S J ET AL: "Natural product-derived small molecule activators of the Trk neurotrophin receptors", SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 27, no. 1, 2001, 31st Annual Meeting of the Society for Neuroscience;San Diego, California, USA; November 10-15, 2001, pages 356, XP001172844, ISSN: 0190-5295 *
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6972335B2 (en) 1996-12-03 2005-12-06 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7759374B2 (en) 2002-08-23 2010-07-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US7875638B2 (en) 2002-08-23 2011-01-25 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US8110590B2 (en) 2002-08-23 2012-02-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US8513429B2 (en) 2002-08-23 2013-08-20 Sloan-Kettering Insitute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US8673949B2 (en) 2008-04-24 2014-03-18 Bristol-Myers Squibb Company Use of epothilone D in treating Tau-associated diseases including Alzheimer's disease

Also Published As

Publication number Publication date
AU2003260723A1 (en) 2004-03-03

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