WO2005105063A1 - Compositions pharmaceutiques contenant des s.e.r.m. et utilisees dans le traitement de la maladie d'alzheimer - Google Patents

Compositions pharmaceutiques contenant des s.e.r.m. et utilisees dans le traitement de la maladie d'alzheimer Download PDF

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Publication number
WO2005105063A1
WO2005105063A1 PCT/EP2004/050682 EP2004050682W WO2005105063A1 WO 2005105063 A1 WO2005105063 A1 WO 2005105063A1 EP 2004050682 W EP2004050682 W EP 2004050682W WO 2005105063 A1 WO2005105063 A1 WO 2005105063A1
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WO
WIPO (PCT)
Prior art keywords
serms
raloxifene
treatment
disease
alzheimer
Prior art date
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PCT/EP2004/050682
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English (en)
Inventor
Alessandro Peri
Susanna Benvenuti
Paola Luciani
Mario Serio
Original Assignee
Universita' Degli Studi Di Firenze
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.)
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Publication date
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Priority to PCT/EP2004/050682 priority Critical patent/WO2005105063A1/fr
Publication of WO2005105063A1 publication Critical patent/WO2005105063A1/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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention refers to a new therapeutic application of drugs named Selective Estrogen Receptor Modulators (SERMs), in particular for the treatment of Alzheimer's disease.
  • SERMs Selective Estrogen Receptor Modulators
  • AD Alzheimer's disease
  • ⁇ A extracellular ⁇ -amyloid
  • ⁇ A The toxicity of ⁇ A is mediated by its interaction with the cell membrane, which results in calcium influx and loss of intracellular calcium homeostasis. Changes in the lipid composition of the neuronal membrane may therefore facilitate ⁇ A toxicity. Indeed, it has been recently demonstrated in a feocromocitoma cell line (PC12) that the cells became resistant to ⁇ A citotoxicity when the surface membrane was enriched in cholesterol levels. Conversely, the cells were more vulnerable to the action of ⁇ A after cholesterol extraction or by inhibiting the de novo synthesis. The hypothesis is that cholesterol deprivation modifies the fluidity of the plasma membrane, thus promoting the incorporation and pore formation of ⁇ A into cell membranes.
  • PC12 feocromocitoma cell line
  • seladin-1 for Selective Alzheimer's Disease lndicator-1
  • seladin-1 for Selective Alzheimer's Disease lndicator-1
  • overexpression of seladin-1 in brain tumoral cells conferred protection against ⁇ A-mediated toxicity and from oxidative stress.
  • seladin-1 effectively inhibited caspase 3 activity, a key mediator of apoptosis, and protected from apoptotic death.
  • This gene has marked sequence homology to the Diminuto/Dwarfl gene, described in plants (i.e. Arabidopsis thaliana) and in Caenorhabditis elegans.
  • Diminuto/Dwarfl gene is an enzyme required for the synthesis of brassinosteroids, which are plant sterols essential for normal growth and development.
  • seladin-1 has enzymatic activity, too.
  • this gene encodes 3-beta-hydroxysterol delta-24-reductase (DHCR24), which catalyzes the reduction of the delta 24 double bond in desmosterol to produce cholesterol. Mutations of this gene have been found in desmosterolosis, a rare severe multiple-conge ⁇ ital- anomaly syndrome, including developmental and growth retardation.
  • Desmosterolosis belongs to a growing group of genetic diseases due to defective cholesterol synthesis, in which mental and psychomotor retardation are constantly observed, thus supporting the hypothesis that cholesterol plays an important role in preserving neuronal cell integrity.
  • an effective pharmacological approach for the prevention or treatment of AD does not exist so far.
  • AD is more common in women and decreased estrogen levels after menopause is a risk factor for the disease.
  • estrogen treatment may decrease the risk or delay the onset of AD in post-menopausal women.
  • Other pharmaceutical compounds, which interact with estrogen receptors have been designed over the years.
  • SERMs Selective Estrogen Receptor Modulators
  • SERMs might turn out to be very interesting drugs for the treatment of neurodegenerative diseases, considering also the fact that estrogen/progesterone replacement therapy in post-menopausal women has been shown to increase the risk of breast cancer. Noticeably, in 2002 the estrogen plus progestin therapy in the Women's Health Initiative trial was discontinued because of breast cancer risk.
  • the neuroprotective effect of the SERMs in particular tamoxifen and raloxifene
  • the first model was represented by neuroblast long-term cell cultures from human fetal olfactory epithelium, previously established, cloned and propagated (1 , 2).
  • FNC show unique features, because they synthesize both neuronal proteins and olfactory markers and respond to odorant stimuli, suggesting their origin from the stem cell compartment that generates mature olfactory receptor neurons, the only type of neuron in the olfactory epithelium.
  • FNC cells express both the subtypes of estrogen nuclear receptors (ER), i.e. and ⁇ (2).
  • ER estrogen nuclear receptors
  • MSC mesenchimal stem cells
  • the response of neuronal cells to estrogen [17 ⁇ -estradiol (17 ⁇ E 2 )] or SERMs (tamoxifen and raloxifene) exposure was evaluated by different experimental procedures. A wide range of concentrations was used (100 pM-100 nM). Neuronal cell growth was assessed by both 3 H-thymidine incorporation assay and cell counting. We found a stimulatory effect of estrogen on ⁇ H-thymidine uptake, which was statistically significant at all the tested concentrations (100 pM-100 nM). With regard to cell counting, a biphasic effect was observed.
  • raloxifene did not protect against ⁇ A- induced toxicity (Fig. 1C). It is worth noting that the peak plasma concentration of tamoxifen or raloxifene, following chronic administration at the therapeutic daily dosage of 20 mg tamoxifen (breast cancer) and 60 mg raloxifene (osteoporosis) orally, is 213 nM and 2.66 nM, respectively (according to the reports of U.S. Food and Drug Administration, Center for Drug Evaluation and Research). Therefore, very low doses of tamoxifen/raloxifene should warrant a neuroprotective effect in the clinical setting for the prevention/treatment of neurodegenerative diseases.
  • sequences of seladin-1 primers spanning 88 bp were: 5'- ATCGCAGCTTTGTGCGATG-3' (sense, exon 4, 5'-end at position 686); 5'- CACCAGGAAACCCAGCGT-3' (antisense, exon 5, 5' -end at position 774).
  • a calibration curve was generated using serial dilutions of a single-stranded sense oligodeoxynucleotide spanning the sequence included between the primers.
  • the results were expressed as fg seladin-1 mRNA/ ⁇ g total RNA.
  • the results are shown in Fig. 2 and indicate that the amount of seladin-1 mRNA in untreated cells was 112 fg/ ⁇ g total RNA. 17 ⁇ E 2 was able to significantly increase seladin-1 expression at all the concentrations that were used.
  • both raloxifene and tamoxifen significantly increased the level of seladi ⁇ -1 expression (152 + 5% and 176 + 6%, mean + SE, respectively, vs control, considered as 100%, at 1 nM, as shown in Fig. 2), with the exception of raloxifene at high concentrations.
  • the active principle could be used in lower quantities.
  • formulation containing as active compound raloxifene can be used as pills for oral administration containing 5-10 mg of active principle.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur une nouvelle application thérapeutique de médicaments, appelés modulateurs sélectifs des récepteurs d'oestrogènes (SERM), notamment dans le traitement de la maladie d'Alzheimer.
PCT/EP2004/050682 2004-05-03 2004-05-03 Compositions pharmaceutiques contenant des s.e.r.m. et utilisees dans le traitement de la maladie d'alzheimer WO2005105063A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2004/050682 WO2005105063A1 (fr) 2004-05-03 2004-05-03 Compositions pharmaceutiques contenant des s.e.r.m. et utilisees dans le traitement de la maladie d'alzheimer

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2004/050682 WO2005105063A1 (fr) 2004-05-03 2004-05-03 Compositions pharmaceutiques contenant des s.e.r.m. et utilisees dans le traitement de la maladie d'alzheimer

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WO2005105063A1 true WO2005105063A1 (fr) 2005-11-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009140665A2 (fr) * 2008-05-16 2009-11-19 Vanda Pharmaceuticals, Inc. Procédé de traitement
JP2012527484A (ja) * 2009-05-21 2012-11-08 ジャイナ ファーマシューティカルズ，インコーポレーテッド 哺乳動物疾患の治療におけるエンドキシフェンの方法および組成物
EP3613418A1 (fr) * 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0659418A1 (fr) * 1993-12-21 1995-06-28 Eli Lilly And Company 2-Phényl-3-azoylbenzothiophènes pour traiter la maladie d'Alzheimer
EP0797990A2 (fr) * 1993-04-10 1997-10-01 Altramed Holdings Ltd. Utilisation d'antagonistes de stéroide pour le traitement et prophylaxe des desordres relatifs à la démence
WO1998048784A2 (fr) * 1997-04-28 1998-11-05 The University Of British Columbia Methodes et composition de modulation de l'amyloidose
EP0976404A2 (fr) * 1998-07-30 2000-02-02 Pfizer Products Inc. Compositions pharmaceutiques pour la prévention et la therapie de troubles cognitifes chez les mammifères
US20010041745A1 (en) * 1999-04-08 2001-11-15 Bryant Henry Uhlman Methods for increasing levels of acetylcholine
WO2003072092A1 (fr) * 2002-02-21 2003-09-04 Harry Fisch Procedes de traitement de carence androgenique chez l'homme au moyen d'anti-estrogenes selectifs

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0797990A2 (fr) * 1993-04-10 1997-10-01 Altramed Holdings Ltd. Utilisation d'antagonistes de stéroide pour le traitement et prophylaxe des desordres relatifs à la démence
US6232350B1 (en) * 1993-04-10 2001-05-15 Altramed Holdings, Ltd. Preparation and method for the treatment and prevention of dimentia disorders
EP0659418A1 (fr) * 1993-12-21 1995-06-28 Eli Lilly And Company 2-Phényl-3-azoylbenzothiophènes pour traiter la maladie d'Alzheimer
WO1998048784A2 (fr) * 1997-04-28 1998-11-05 The University Of British Columbia Methodes et composition de modulation de l'amyloidose
EP0976404A2 (fr) * 1998-07-30 2000-02-02 Pfizer Products Inc. Compositions pharmaceutiques pour la prévention et la therapie de troubles cognitifes chez les mammifères
US20010041745A1 (en) * 1999-04-08 2001-11-15 Bryant Henry Uhlman Methods for increasing levels of acetylcholine
WO2003072092A1 (fr) * 2002-02-21 2003-09-04 Harry Fisch Procedes de traitement de carence androgenique chez l'homme au moyen d'anti-estrogenes selectifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GURSOY, ERDAL ET AL: "Tamoxifen protects clonal mouse hippocampal (HT-22) cells against neurotoxins-induced cell death", NEUROCHEMISTRY INTERNATIONAL , 40(5), 405-412 CODEN: NEUIDS; ISSN: 0197-0186, 2002, XP008041030 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009140665A2 (fr) * 2008-05-16 2009-11-19 Vanda Pharmaceuticals, Inc. Procédé de traitement
WO2009140665A3 (fr) * 2008-05-16 2010-01-28 Vanda Pharmaceuticals, Inc. Procédé de traitement
JP2011520920A (ja) * 2008-05-16 2011-07-21 ヴァンダ ファーマシューティカルズ インコーポレイテッド 治療方法
JP2012527484A (ja) * 2009-05-21 2012-11-08 ジャイナ ファーマシューティカルズ，インコーポレーテッド 哺乳動物疾患の治療におけるエンドキシフェンの方法および組成物
EP3613418A1 (fr) * 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Procédés et compositions de modulation des niveaux d'hormones
US10874638B2 (en) 2014-01-17 2020-12-29 Ligand Pharmaceuticals Incorporated Methods and compositions for modulating hormone levels

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