WO2024263638A2 - Composition pharmaceutique et utilisations de celle-ci - Google Patents

Composition pharmaceutique et utilisations de celle-ci Download PDF

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Publication number
WO2024263638A2
WO2024263638A2 PCT/US2024/034614 US2024034614W WO2024263638A2 WO 2024263638 A2 WO2024263638 A2 WO 2024263638A2 US 2024034614 W US2024034614 W US 2024034614W WO 2024263638 A2 WO2024263638 A2 WO 2024263638A2
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WO
WIPO (PCT)
Prior art keywords
flavonoid
antithrombosis
pharmaceutical composition
derivative
drug
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/US2024/034614
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English (en)
Other versions
WO2024263638A3 (fr
Inventor
I-Fan Wang
Hsiang-Yu Chang
Chen-Hung Ting
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.)
Yeefan Med Inc
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Yeefan Med Inc
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Publication date
Application filed by Yeefan Med Inc filed Critical Yeefan Med Inc
Publication of WO2024263638A2 publication Critical patent/WO2024263638A2/fr
Publication of WO2024263638A3 publication Critical patent/WO2024263638A3/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to pharmaceutical compositions and methods for the treatment of normal aging and proteinopathies including neurodegenerative diseases by reducing misfolded proteins of disease associated proteins.
  • AD Alzheimer’s disease
  • PD Parkinson disease
  • ALS amyotrophic lateral sclerosis
  • FTLD-U frontotemporal lobar degeneration with ubiquitin-positive inclusions
  • DLB Dementia Lewy Bodies
  • Parkinson disease is a progressive neurodegenerative disorder primarily affected motor system, usually occurred of rigidity, hypokinesia and tremor. Non-motor symptoms also developed as the disease worsens, including cognitive changes. PD is caused predominantly by the loss of dopaminergic neurons in the substantia nigra (SN), a basal ganglia structure located in the midbrain.
  • the signature pathology of the PD is lewy bodies (LBs). Misfolded alpha-synuclein (a-Syn) as the major component of the LBs observed in sporadic PD; and that mutations in the a-Syn are associated with some rare familiar PD.
  • the second risk factor for PD is the Leucine-rich repeat kinase 2 (LARRK2).
  • LARRK2 gene mutation accounts for 5% of familiar PD as well as 3% of sporadic cases.
  • LRRK2 harbored G2019 mutation is more susceptible to forming a-Syn inclusions that links LRRK2 with protein-misfolding pathology.
  • the diagnostic process often takes over a year to complete, and currently no methods is available for early diagnostic and monitoring disease progression.
  • the medical community is still faced with the challenge of treating numerous types of neurodegenerative diseases. Accordingly, there is still a need for a more effective and safe treatment for neurodegenerative diseases.
  • the present invention addresses this need.
  • compositions are provided herein: a composition comprising a antithrombosis drug; a composition comprising a flavonoid; a composition comprising a blood pressure medicine; a composition comprising a combination of a antithrombosis drug and a flavonoid; a composition comprising a combination of a antithrombosis drug and a blood pressure medicine; a composition comprising a combination of a blood pressure medicine and a flavonoid; or a composition comprising a combination of a antithrombosis drug, a flavonoid and a blood pressure medicine.
  • each of these combinations improves synucleinopathy-related symptoms and cognition decline. It has been discovered that these combinations achieve reduction of a-Syn-misfolded proteins by synergistic effects.
  • Methods for reducing misfolded aggregates by administering a therapeutic agent to a cell, a tissue or a subject are also provided herein.
  • synucleinopathies include, but not limited to AD, Parkinson disease dementia (PDD), Dementia with Lewy body (DLB), Parkinson disease without dementia, and multiple system atrophy (MSA).
  • AD Parkinson disease dementia
  • DLB Dementia with Lewy body
  • MSA multiple system atrophy
  • Fig.l is an assembly of images illustrating an analysis of longitudinal tracking of a-Syn, p-TDP-43, tau, beta-amyloid, and novel identified biomarkers of AD and PD from a single patient with synucleinopathies by b-isox based ELISA.
  • compositions and methods for treating neurodegenerative diseases are described herein.
  • the compositions can be selected from a composition comprising a composition comprising a antithrombosis drug; a composition comprising a flavonoid; a composition comprising a blood pressure medicine; a composition comprising a combination of a antithrombosis drug and a flavonoid; a composition comprising a combination of a antithrombosis drug and a blood pressure medicine; a composition comprising a combination of a blood pressure medicine and a flavonoid; or a composition comprising a combination of a antithrombosis drug, a flavonoid and a blood pressure medicine.
  • each of these various combinations synergistically reduces plasma a-Syn level.
  • methods are described herein for reducing plasma a-Syn in a cell, a tissue or a subject by administering an effective amount of a therapeutic agent in the cell, the tissue or the subject to reduce the level of a-Syn misfolded proteins.
  • the therapeutic agent is a flavonoid.
  • the therapeutic agent is the pharmaceutical composition described herein.
  • treating includes preventative (e.g. prophylactic), palliative, and curative uses or results.
  • reducing includes slowing or stopping the formation of a-Syn aggregates, or disassembling the a-Syn misfolded aggregates that have already been formed.
  • therapeutic intervention refers broadly to actions taken that are expected to yield healing results, symptoms improvement or health restoration.
  • the term “amount” is used in this document to denote the quantity or distribution of something.
  • the present invention can utilize any of the foregoing information falling within the meaning of the term “amount” in relation to one or more proteins, as well as classes and subclasses of such proteins. Combination of such information on the amount of proteins can be referred to as “pattern.”
  • subject typically refers to a human or an animal having conformational disease or suspected of having conformational disease. It is to be understood that a subject can be subjects without known or suspected conformation disease, such as research subjects, are also included within the scope of the term “subject.”
  • flavonoid includes a flavone, which includes baicalein originally isolated from the roots of Scutellaria baicalensis.
  • Baicalein is an inhibitor of CYP2C9, an enzyme of the cytochrome P450 system that metabolizes drugs in the body.
  • the flavonoid includes baicalein and its derivatives.
  • synucleinopathies typically refers to a group of neurodegenerative disorders characterized by the accumulation of misfolded a-Syn proteins in cell bodies of neurons and glia.
  • Disorders with synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA).
  • PD Parkinson's disease
  • DLB dementia with Lewy bodies
  • PAF pure autonomic failure
  • MSA multiple system atrophy
  • compositions for treating symptoms of synucleinopathies are provided herein.
  • the pharmaceutical compositions provided herein are useful for reducing misfolded proteins.
  • the pharmaceutical composition includes a flavonoid, such as baicalein, a derivative thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof in combination with a antithrombosis drug, such as clopidogrel sulphate, a derivative thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • a blood pressure medication such as amlodipine, a derivative thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the flavonoid such as baicalein or its derivative
  • the flavonoid is dosed in an amount ranging from about 100 mg to about 2000 mg per day, or 100 mg to 2000 mg per day.
  • Reagents and Antibodies were purchased from Sigma and Dalton dissolved in dimethyl sulfoxide (DMSO).
  • the primary antibodies against CAI (#MBS 1492724), FAM20C (#MBS76921 1), VAT1L (#MBS 1492099), SPTA1 (#MBS9417174), C4BPB (#MBS9125430) and PRDX2 (#MBS7046127) were purchased from Mybiosource.
  • b-isox-ELISA procedures Blood samples were firstly collected through Blood Collection Tubes. Centrifugation of the tubes for 15 min at 2,200xg. The resulting supernatant (upper layer) as the plasma sample. Before immunoassay, gently mixed l OOpL plasma (or CSF) with I pL b-isox through pipetting and rotated for Ih at 4°C. Wash each streptavidin-coated microwell 3 times by 200pL wash buffer (WB/(25mM Tris, 150mM NaCl; pH 7.2), 0.1% BSA, 0.05% Tween®-20) (do not allow wells to dry).
  • WB/(25mM Tris, 150mM NaCl; pH 7.2) 0.1% BSA, 0.05% Tween®-20
  • Example 1 A pilot clinical trial in synucleinopathy: A combination of baicalein, clopidogrel sulphate and amlodipine
  • b-isox based-ELISA for diagnostic, real-time pathophysiological monitoring and pharmacometric measurements of a combination of baicalein, clopidogrel sulphate and amlodipine.
  • the patient saw a 50% reduction in plasma a-Syn and novel identified biomarkers of PD after 4 weeks and a 100% reduction after 16 weeks and demonstrated significant cognitive gain on behavior over the course of treatment.
  • the patient received 500 mg of baicalein orally twice a day for 5 days and 500 mg of baicalein orally once a day for 5 days and was assessed for the primary outcome of change from baseline of plasma a-Syn levels and PD related biomarkers by b-isox -based ELISA. Meanwhile, the patient takes Norvasc (2.5 mg) and PLAVIX film-coated tablets (75 mg) daily.
  • Baicalein, Clopidogrel Sulphate and Amlodipine can be given as an easy-to-administer oral tablet that has shown potential for robust efficacy with a favorable safety profile.

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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

Sont présentement décrites des compositions pharmaceutiques et des méthodes de traitement, de détection, de caractérisation et de réduction de protéines de mauvais repliement et de prévention de maladies associées telles que des maladies neurodégénératives et un vieillissement normal.
PCT/US2024/034614 2023-06-20 2024-06-19 Composition pharmaceutique et utilisations de celle-ci Ceased WO2024263638A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363521954P 2023-06-20 2023-06-20
US63/521,954 2023-06-20

Publications (2)

Publication Number Publication Date
WO2024263638A2 true WO2024263638A2 (fr) 2024-12-26
WO2024263638A3 WO2024263638A3 (fr) 2025-04-17

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PCT/US2024/034614 Ceased WO2024263638A2 (fr) 2023-06-20 2024-06-19 Composition pharmaceutique et utilisations de celle-ci

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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2004155T3 (en) * 2006-03-29 2018-04-30 Wista Lab Ltd PROTEIN AGGREGATION INHIBITORS
US20110111014A1 (en) * 2007-06-26 2011-05-12 Parkinson's Institute Methods and compositions for treatment of neurological disorders
CA2844670A1 (fr) * 2011-08-12 2013-02-21 Salk Institute For Biological Studies Analogues du polyphenol neuroprotecteurs
WO2023019351A1 (fr) * 2021-08-16 2023-02-23 University Health Network Méthodes et compositions pour le traitement de la neurodégénérescence induite par l'alpha-synucléine

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