EP0912602A1 - Procede de traitement des troubles lies a la presence de peptide beta-amyloide au moyen de thyroliberine - Google Patents

Procede de traitement des troubles lies a la presence de peptide beta-amyloide au moyen de thyroliberine

Info

Publication number
EP0912602A1
EP0912602A1 EP97904903A EP97904903A EP0912602A1 EP 0912602 A1 EP0912602 A1 EP 0912602A1 EP 97904903 A EP97904903 A EP 97904903A EP 97904903 A EP97904903 A EP 97904903A EP 0912602 A1 EP0912602 A1 EP 0912602A1
Authority
EP
European Patent Office
Prior art keywords
releasing hormone
amyloid peptide
thyrotropin releasing
amyloid
analog
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Withdrawn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
EP97904903A
Other languages
German (de)
English (en)
Other versions
EP0912602A4 (fr
Inventor
Kimberly S. Fuson
Patrick C. May
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
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 Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0912602A1 publication Critical patent/EP0912602A1/fr
Publication of EP0912602A4 publication Critical patent/EP0912602A4/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Withdrawn legal-status Critical Current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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/066—TRH, thyroliberin, thyrotropin releasing hormone
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

Definitions

  • Alzheimer's disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Proteinaceous deposits (called "amyloid”) appear as neurofibrillary tangles, amyloid plaque cores, and amyloid of the congophilic angiopathy. [For reviews, see, Alzheimer's Disease. (B.
  • ⁇ -amyloid peptide is proteolytically derived from a transmembrane protein, the amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • ⁇ -Amyloid peptide consists, in its longest forms, of 42 or 43 amino acid residues. J. Kang, et al.. Nature (London). 325:733-736 (1987). These peptides, however, vary as to their amino-termini. C. Hilbich, et al.. Journal of Molecular Biology. 218:149-163 (1991). Because senile plaques are invariably surrounded by dystrophic neurites, it was proposed early that ⁇ -amyloid peptide is involved in the loss of neuronal cells that occurs in Alzheimer's disease. B.
  • Thyrotropin releasing hormone is a naturally occurring tripeptide having the sequence
  • Thyrotropin releasing hormone also has a central role in the regulation of the hypothalmic-pituitary-thyroid axis. In addition to its role in the regulation of thyroid function, thyrotropin releasing hormone has long been recognized as a modulatory neuropeptide, with a broad spectrum of central nervous system activity. Abundant extra-hypothalmic TRH receptors have been demonstrated in both rodent and human brain. Although TRH interacts with several classical neurotransmitters, the most robust evidence is for a positive modulatory effect of TRH on the action of acetylcholine in the central nervous system.
  • Thyrotropin releasing hormone has been reported to have antidepressant properties and to be beneficial in schizophrenia. These studies have, however, proven to be controversial.
  • This invention provides methods for the treatment of Alzheimer's disease and other conditions associated with ⁇ -amyloid peptide in mammals. Specifically, this invention provides methods of using thyrotropin releasing hormone, or an analog thereof, for the treatment of a condition associated with ⁇ -amyloid-induced neurodegeneration.
  • This invention provides a method for treating a physiological disorder associated with ⁇ -amyloid peptide in a mammal which comprises administering to a mammal in need thereof an effective amount of thyrotropin releasing hormone, an analog of thyrotropin releasing hormone, or a salt or prodrug of thyrotropin releasing hormone or said analog.
  • ⁇ -amyloid peptide naturally occurs as a series of peptides which are 39 to 43 amino acids long, with the shorter, more soluble forms being present in cerebrovascular deposits and the longer forms being found primarily in senile plaques.
  • the primary structure ofthe 43 amino acid long peptide ( ⁇ l-43) is depicted in SEQ ID NO:l:
  • ⁇ -amyloid peptide comprising amino-truncated, carboxy- truncated, or internal deletions, or any combination of these, as well as conservative variants of these peptides, may be employed in this invention so long as that peptide fragment demonstrates the requisite neurotoxicity.
  • ⁇ -amyloid peptide While the peptide of SEQ ID NO:l and SEQ ID NO:2 are referred to as ⁇ -amyloid peptide throughout this document, in the body of literature concerning this field, this peptide is alternatively referred to as ⁇ -amyloid protein, amyloid ⁇ peptide, amyloid ⁇ A4, ⁇ protein, amyloid A4, ⁇ -peptide, and other such names.
  • treating includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
  • effective amount refers to the amount of compound necessary to treat physiological effects or disorders associated with ⁇ -amyloid peptide, or inhibit amyloidogenic production or deposition, or treat Alzheimer's Disease, as the case may be.
  • ⁇ -amyloid peptide includes diseases related to the inappropriate or undesirable deposition of ⁇ -amyloid peptide, and as such includes Alzheimer's Disease (including familial Alzheimer's Disease), Down's Syndrome, advanced aging of the brain, hereditary cerebral hemorrhage with amyloidosis of the Dutch-type (HCHWA-D), and the like.
  • the compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • This invention also encompasses methods employing the pharmaceutically acceptable salts of the compounds described herein.
  • a compound employed in this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • This invention also encompasses methods employing the pharmaceutically acceptable solvates of the compounds described herein. Many of these compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • A represents, with the nitrogen and carbon atoms to which it is linked, a 2-oxoperhydro-7-azepinyl group, a 2- oxoperhydro-8-azocinyl group, a 2-oxoperhydro-9-azoninyl group, a 2-oxoperhydro-lO-azinyl group, a 2-oxo-2,3,4,7- tetrahydrobenz[e]azepin-7-yl group, a 2-oxo-2,3,6,7- tetrahydrobenz[d]azepin-7-yl group, or a 2- ⁇ xo-2,3,6,7- tetrahydrobenz[c]azepin-7-yl group;
  • B represents, with the nitrogen and carbon atoms to which it is linked, a polycyclic structure selected from the following structures,
  • 2-azabicyclo[2.2.2]octane optionally substituted at positions 1 and 4 with one or two linear or branched (C1-C 4 ) alkyl groups;
  • pyrrolidine optionally substituted with one or two linear or branched (C 1 -C 4 ) alkyl groups;
  • R represents:
  • a (4-imidazolyl)methyl group optionally substituted on one of the nitrogen atoms with a linear or branched (C 1 -C 4 ) alkyl radical;
  • A represents, with the nitrogen and carbon atoms to which it is linked, a cycloamide group selected from the list consisting of
  • B represents, with the nitrogen and carbon atoms to which it is linked, a polycyclic structure selected from the following structures,
  • 2-azabicyclo[2.2.2]octane optionally substituted at positions 1 and 4 with one or two linear or branched (C 1 -C 4 ) alkyl groups;
  • R represents:
  • a linear or branched (Ci-C ⁇ ) alkyl group optionally substituted with an amino group or a guanidino group; or a (4-imidazolyl)methyl group, optionally substituted on one of the nitrogen atoms with a linear or branched (C1-C 4 ) alkyl radical;
  • the neuroprotective ability of thyrotropin releasing hormone is demonstrated by assays showing the ability of thyrotropin releasing hormone to protect neural cells from the neurotoxic effects of beta amyloid peptide. Such assays are described below.
  • ED 18 cortical cells are seeded into polyethylenimine-coated tissue culture dishes and cultured for 3-5 days in vitro before treatment with a 25 ⁇ M solution of ⁇ -amyloid peptide, either freshly dissolved (predominantly random coil conformation) or aged (7 days, predominantly ⁇ -sheet conformation).
  • This neurotoxicity assay is conducted in chemically-defined HEPES-buffered DMEM supplemented with fetal calf serum.
  • ED 18 cortical cells are seeded into polyethylenimine-coated tissue culture dishes and cultured for 3-5 days in vitro. This assay is conducted in chemically-defined HEPES-buffered DMEM supplemented with fetal calf serum.
  • DMEM Dulbecco's Modified Eagle's Medium
  • the cells are incubated for 10 days in vitro before treatment with a 25 ⁇ M solution of ⁇ -amyloid peptide, either freshly dissolved or aged. After four days of incubation, cell integrity is determined by measuring the level of the enzyme lactate dehydrogenase (LDH) using a standard colorimetric endpoint assay for pyruvate.
  • LDH lactate dehydrogenase
  • thyrotropin releasing hormone is neuroprotective again ⁇ -amyloid peptide-induced toxicity in a dose- dependent manner with an approximate IC50 in the nanomolar range (10 nM-100 nM).
  • the alamarBlueTM assay incorporates a proprietary fluorometric/colorimetric growth indicator (Alamar Biosciences, Inc.) based on the detection of metabolic activity. Viable cells cause alamarBlueTM to change from an oxidized (non-fluorescent, blue color) to a reduced (fluorescent, red) form. Neuronal viability as assessed by alamarBlueTM is comparable in sensivity to that obtained by measuring the release of LDH into the culture media or the reduction ofthe tetrazolium salt XTT. Assays are performed by replacing the culture media with a 10% alamarBlueTM solution in neuronal medium.
  • alamarBlueTM Reduction of alamarBlueTM is determined using a Millipore Cytofluor 2350 Scanner (excitation, 560 nm; emission, 590 nm) and CytoCalcTM software (v. 01.00.04, Millipore Corporation). Results are expressed as percent of control (untreated) cultures.
  • the conversion of the tetrazolium to the formazan is a measure of the reducing potential of the mitochondria and, hence, a measure of cell viability.
  • Exposure of PC 12 cells to ⁇ -amyloid peptide (1-40) or a sub- fragment ⁇ -amyloid peptide (25-35) led to about a 50% reduction in the amount of formazan production.
  • Thyrotropin releasing hormone prevents the reduction in MTT conversion observed in the presence of ⁇ - amyloid peptide.
  • ⁇ -amyloid peptide results in the activation of immune and inflammatory responses in affected areas of the brain.
  • the ⁇ -amyloid peptide upon assuming the conformation necessary for aggregation, also potentiates cytokine secretion, especially interleukin-6 and interleukin-8 release.
  • Thyrotropin releasing hormone in preventing the formation of ⁇ -amyloid aggregates, inhibits this cytokine release and, thereby, ameliorates the inflammatory component of Alzheimer's Disease.
  • thyrotropin releasing hormone is useful in treating Alzheimer's disease may be made by the utilization of several assays which are known in the art.
  • An additional assay which may be employed involves the use of a transgenic mouse model as described in D. Games, et al.. Nature (London), 373:523-527 (1995).
  • the ability of thyrotropin releasing hormone to ameliorate the inflammatory aspects of Alzheimer's disease may be rapidly assessed using this mouse model.
  • compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention may be effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the instant invention further provides pharmaceutical formulations comprising the claimed compounds.
  • the compounds preferably in the form of a pharmaceutically acceptable salt, can be formulated for oral or parenteral administration.
  • the compounds can be admixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers and the like.
  • the compositions comprising TRH compounds will contain from about 0.1 to 90% by weight of the active compound, and more generally from about 10 to 30%.
  • the compositions may contain common carriers and excipients such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid.
  • Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, corn starch, sodium starch, glycolate and alginic acid.
  • Tablet binders that can be included are acacia, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.
  • Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
  • Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring, or the like can also be used.
  • a water soluble form of compounds of the formula 1 can be dissolved in one of the commonly used intravenous fluids and administered by infusion.
  • Such fluids for example, physiological saline, Ringer's solution or 5% dextrose solution can be used.
  • a sterile formulation of a suitable soluble salt form of the compounds of the formula 1, for example the hydrochloride salt can be dissolved and administered in a pharmaceutical diluent such as pyrogen-free water (distilled), physiological saline or 5% glucose solution.
  • a suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate.
  • a sterile formulation of a suitable salt form of TRH for example, the hydrochloride salt, formulated in a diluent such as distilled or deionized water, is particularly useful.
  • a preferred formulation of the compounds of the present invention includes the use of poly( alkyl cyanoacrylate) particles, commonly known as nanoparticles, as carriers for the TRH protein.
  • nanoparticles are well known in the art as described in J.L. Grangier, et ai. "Nanoparticles as carriers for growth hormone releasing factor", Journal of Controlled Release. 15:3-13 (1991).
  • the unit dosage form of the compound can be solution of the compound, preferably in its salt form, in a suitable diluent in sterile hermetically sealed ampoules.
  • concentration of the compound in the unit dosage may vary, e.g. from about 1% to about 50% depending on the particular form of the compound and its solubility and the dose desired by the physician.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention se rapporte à un procédé de traitement d'un trouble physiologique associé à la présence d'un peptide bêta-amyloïde chez un mammifère. Ledit procédé consiste à administrer à un mammifère ayant besoin d'un tel traitement, une quantité efficace de thyrolibérine (TRH), un analogue de thyrolibérine, ou un sel ou un bioprécurseur de thyrolibérine ou dudit analogue.
EP97904903A 1996-02-05 1997-02-05 Procede de traitement des troubles lies a la presence de peptide beta-amyloide au moyen de thyroliberine Withdrawn EP0912602A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1112696P 1996-02-05 1996-02-05
US11126P 1996-02-05
PCT/US1997/001481 WO1997028184A1 (fr) 1996-02-05 1997-02-05 Procede de traitement des troubles lies a la presence de peptide beta-amyloide au moyen de thyroliberine

Publications (2)

Publication Number Publication Date
EP0912602A1 true EP0912602A1 (fr) 1999-05-06
EP0912602A4 EP0912602A4 (fr) 2002-09-11

Family

ID=21748996

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97904903A Withdrawn EP0912602A4 (fr) 1996-02-05 1997-02-05 Procede de traitement des troubles lies a la presence de peptide beta-amyloide au moyen de thyroliberine

Country Status (5)

Country Link
EP (1) EP0912602A4 (fr)
JP (1) JP2000505425A (fr)
AU (1) AU1757597A (fr)
CA (1) CA2245145A1 (fr)
WO (1) WO1997028184A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4725581A (en) * 1985-08-05 1988-02-16 Adir Et Compagnie New peptide compounds having a lactone or cycloamide structure
US5098888A (en) * 1989-06-29 1992-03-24 Adir Et Compagnie New heterocyclic tripeptide compounds
US5190923A (en) * 1990-06-18 1993-03-02 Adir Et Compagnie Peptide compounds containing a cyclic amide structure

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1540574A (en) * 1975-05-23 1979-02-14 Takeda Chemical Industries Ltd Medicament for remedying schizophrenia
JPS57188526A (en) * 1981-05-14 1982-11-19 Takeda Chem Ind Ltd Peptide-containing pharmaceutical preparation
IT1237435B (it) * 1989-12-14 1993-06-04 Farmaco attivo nel ripristino della plasticita' neuronale.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4725581A (en) * 1985-08-05 1988-02-16 Adir Et Compagnie New peptide compounds having a lactone or cycloamide structure
US5098888A (en) * 1989-06-29 1992-03-24 Adir Et Compagnie New heterocyclic tripeptide compounds
US5190923A (en) * 1990-06-18 1993-03-02 Adir Et Compagnie Peptide compounds containing a cyclic amide structure

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MELLOW A M ET AL: "A PILOT STUDY OF INTRAVENOUS TRH IN ALZHEIMER'S DISEASE" ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1989, pages 618-619, XP001087750 ISSN: 0077-8923 *
MELLOW A M ET AL: "ACUTE EFFECTS OF HIGH-DOSE TRH INFUSIONS IN ALZHEIMER'S DISEASE" PSYCHOPHARMACOLOGY, vol. 98, no. 3, 1989, pages 403-407, XP001087699 ISSN: 0033-3158 *
See also references of WO9728184A1 *
YARBROUGH G G ET AL: "THE THERAPEUTIC POTENTIAL OF TRH IN ALZHEIMERS DISEASE" PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, vol. 9, no. 3, 1985, pages 285-289, XP001087686 ISSN: 0278-5846 *

Also Published As

Publication number Publication date
WO1997028184A1 (fr) 1997-08-07
JP2000505425A (ja) 2000-05-09
AU1757597A (en) 1997-08-22
EP0912602A4 (fr) 2002-09-11
CA2245145A1 (fr) 1997-08-07

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