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WO2025080080A1 - Composition pharmaceutique pour prévenir ou traiter la maladie de parkinson, contenant un inhibiteur de pdk en tant que principe actif - Google Patents

Composition pharmaceutique pour prévenir ou traiter la maladie de parkinson, contenant un inhibiteur de pdk en tant que principe actif Download PDF

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Publication number
WO2025080080A1
WO2025080080A1 PCT/KR2024/096275 KR2024096275W WO2025080080A1 WO 2025080080 A1 WO2025080080 A1 WO 2025080080A1 KR 2024096275 W KR2024096275 W KR 2024096275W WO 2025080080 A1 WO2025080080 A1 WO 2025080080A1
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WO
WIPO (PCT)
Prior art keywords
cas
disease
chemical formula
parkinson
pharmaceutical composition
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Pending
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PCT/KR2024/096275
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English (en)
Korean (ko)
Inventor
오요한
김보광
이연종
김희정
백승만
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Sungkyunkwan University
Industry University Cooperation Foundation IUCF HYU
Gyeongsang National University GNU
Original Assignee
Sungkyunkwan University
Industry University Cooperation Foundation IUCF HYU
Gyeongsang National University GNU
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Priority claimed from KR1020240137404A external-priority patent/KR20250051596A/ko
Publication of WO2025080080A1 publication Critical patent/WO2025080080A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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

  • An example of the present invention is:
  • the present invention relates to a pharmaceutical composition for preventing or treating Parkinson's disease, comprising a PDK (pyruvate dehydrogenase kinase) inhibitor as an active ingredient, a pharmaceutical preparation for preventing or treating Parkinson's disease comprising the same, and a method for predicting the therapeutic effect of a candidate drug on Parkinson's disease.
  • PDK pyruvate dehydrogenase kinase
  • Parkinson's disease is a disease that rarely appears before the age of 50 and the incidence increases with age. In particular, the incidence rate is highest between the ages of 85 and 89. Parkinson's disease is the second most common degenerative brain disease in the world after Alzheimer's disease (AD), and is characterized by symptoms such as bradykinesia, tremors, and rigidity. The death of dopaminergic neurons (mDA neurons) located in the substantia nigra (SN) of the midbrain is the main cause of Parkinson's disease. Abnormal protein aggregates called Lewy bodies are commonly observed in the substantia nigra (SN) of Parkinson's disease patients.
  • AD Alzheimer's disease
  • mDA neurons dopaminergic neurons located in the substantia nigra
  • SN substantia nigra
  • Abnormal protein aggregates called Lewy bodies are commonly observed in the substantia nigra (SN) of Parkinson's disease patients.
  • Phosphoinositide 3-kinase (PI3K) and pyruvate dehydrogenase kinase (PDK) are upstream regulators of the autophagy pathway and can affect autophagy activity.
  • PI3K activation induces the production of phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), which activates protein kinase B (AKT).
  • PIP 3 phosphatidylinositol 3,4,5-trisphosphate
  • AKT protein kinase B
  • AKT protein kinase B
  • the purpose is to provide a pharmaceutical composition for preventing or treating Parkinson's disease, comprising a PDK (pyruvate dehydrogenase kinase) inhibitor as an active ingredient.
  • PDK pyruvate dehydrogenase kinase
  • the purpose is to provide a pharmaceutical preparation for preventing or treating Parkinson's disease, comprising the above pharmaceutical composition.
  • C total is the total number of cells in the drug treatment group
  • BA k agg is the area of individual alpha-synuclein aggregates in the untreated group
  • BI k agg is the fluorescence intensity of individual alpha-synuclein aggregates in the drug-untreated group
  • BC total refers to the total number of cells in the untreated group.
  • a pharmaceutical composition for preventing or treating Parkinson's disease comprising a PDK (pyruvate dehydrogenase kinase) inhibitor as an active ingredient.
  • PDK pyruvate dehydrogenase kinase
  • the PDK inhibitor may be at least one selected from the group consisting of GSK2334470 (CAS no. 1227911-45-6), MP7 (CAS no. 1001409-50-2), and OSU03012 (CAS no. 742112-33-0).
  • the GSK2334470 (CAS no. 1227911-45-6) may be a compound of the following chemical formula 1.
  • the MP7 (CAS no. 1001409-50-2) may be a compound of the following chemical formula 2.
  • the OSU03012 (CAS no. 742112-33-0) may be a compound of the following chemical formula 3.
  • the PDK inhibitor may inhibit the death of dopaminergic neurons.
  • a pharmaceutical preparation for preventing or treating Parkinson's disease comprising the pharmaceutical composition above, is provided.
  • the formulation may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
  • the formulation may be in the form of an oral formulation, an injection formulation, an infusion formulation, a spray formulation, or a liquid formulation.
  • a method for predicting the therapeutic effect of a candidate drug on Parkinson's disease is provided using the following [Mathematical Formula 1].
  • a k agg is the area of individual alpha-synuclein aggregates in the drug-treated group
  • I k agg is the fluorescence intensity of individual alpha-synuclein aggregates in the drug-treated group
  • C total is the total number of cells in the drug treatment group
  • BA k agg is the area of individual alpha-synuclein aggregates in the untreated group
  • BI k agg is the fluorescence intensity of individual alpha-synuclein aggregates in the drug-untreated group
  • BC total refers to the total number of cells in the untreated group.
  • the GSK2334470 (CAS no. 1227911-45-6) may be a compound of the following chemical formula 1.
  • the OSU03012 (CAS no. 742112-33-0) may be a compound of the following chemical formula 3.
  • a method for preventing or treating Parkinson's disease comprising administering a PDK inhibitor to a subject in need thereof.
  • a method for preventing or treating Parkinson's disease comprising administering a PDK inhibitor to a subject in need thereof.
  • Figure 2C is a formula for the ⁇ -synuclein comprehensive aggregation score ( ⁇ -CAS).
  • Figure 2D is a representative image of immunocytochemistry staining of pathogenic ⁇ -syn aggregates using 5G4 antibody.
  • Figure 2E is a graph quantifying the degree of pathogenic ⁇ -syn aggregate formation by ⁇ -CAS.
  • Figure 5 shows the results of analyzing the effects of oral administration of GSK2334470 on the inhibition of pathogenic ⁇ -syn aggregate lesions and protection of mDA neurons in a PD mouse model.
  • Figure 5A is a schematic diagram summarizing the schedule for creating a PD mouse model by injecting AAV- ⁇ -syn or AAV-GFP into the SNpc region and ⁇ -syn microfibrils ( ⁇ PFF) or PBS into the VTA region, and evaluating the therapeutic activity through oral administration of GSK2334470.
  • ⁇ PFF ⁇ -syn microfibrils
  • a pharmaceutical composition for preventing or treating Parkinson's disease comprising a PDK (pyruvate dehydrogenase kinase) inhibitor as an active ingredient.
  • PDK pyruvate dehydrogenase kinase
  • PDK is closely related to the regulation of autophagy in neurodegenerative diseases such as Parkinson's disease.
  • PDK When PDK is activated, autophagy is inhibited by activating the AKT and mTORC1 pathways, which may contribute to the accumulation of abnormal protein aggregates such as ⁇ -synuclein.
  • the ULK1 unc-51 like autophagy activating kinase 1
  • PDK inhibition is being studied as an important target that can be expected to have a therapeutic effect by activating the autophagy pathway in diseases such as Parkinson's disease.
  • PDK pyruvate dehydrogenase kinase
  • PDC pyruvate dehydrogenase complex
  • subject means a subject in need of treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, dog, cat, horse, or cow.
  • the pharmaceutical composition may be provided as a pharmaceutical composition or pharmaceutical preparation comprising the active ingredient alone or including one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the term "pharmaceutically acceptable carrier” as used herein is one commonly used in formulations, which may be a colloidal suspension, powder, saline, lipid, liposome, microspheres or nano spherical particles. It also includes, but is not limited to, saline, sterile water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposomes, and the like, and may further include other common additives such as antioxidants and buffers as needed.
  • lipids may form a complex with or be associated with a carrier vehicle, and may be delivered in vivo using a carrier system known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances or fatty acids.
  • a carrier system known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances or fatty acids.
  • each ingredient can be preferably formulated using the methods disclosed in Remington's literature.
  • Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid preparations may be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the composition.
  • excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, and when manufactured in the form of eye drops, known excipients or diluents may be used.
  • the pharmaceutical composition may be administered alone or in combination with other therapeutic agents. That is, the pharmaceutical composition may be administered in combination with a known composition or other agent having a preventive or therapeutic effect on the disease, and may be administered simultaneously, separately, or sequentially, and may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by considering all of the above factors, and this can be easily determined by those skilled in the art.
  • the PDK inhibitor may inhibit the aggregation of pathogenic alpha-synuclein.
  • pathogenic alpha-synuclein refers to a small protein mainly found in neurons of the brain, which is known to play an important role in the signal transmission process between neurons.
  • Alpha-synuclein is involved in the formation and regulation of release of synaptic vesicles, and exists in the form of a soluble monomer under normal conditions.
  • alpha-synuclein is transformed into abnormal aggregates, which are associated with various neurodegenerative diseases.
  • abnormal accumulation of alpha-synuclein occurs in diseases such as Parkinson's disease, Lewy body dementia, and multiple system atrophy.
  • the PDK inhibitor may inhibit the death of dopaminergic neurons.
  • dopaminergic neuron refers to a nerve cell that produces and secretes the neurotransmitter dopamine, which plays a very important role in the central nervous system.
  • Dopaminergic neurons are mainly located in the substantia nigra and ventral tegmental area of the midbrain, and these cells are involved in regulating various brain functions such as motor control, emotion, reward system, and motivation. When dopaminergic neurons are damaged or die, various neurological problems may occur due to insufficient production and transmission of dopamine.
  • liquid formulation refers to a pharmaceutical form that provides a drug in liquid form, and a dosage form that contains an active ingredient in a liquid form.
  • patch used in this specification refers to a preparation that is attached to the skin to continuously exhibit a medicinal effect. Patches have a low risk of side effects such as gastrointestinal disorders or liver disorders caused by oral medication, can be administered to patients who have difficulty taking oral medication, and have the advantage of being able to exhibit the same medicinal effect without side effects with lower doses than oral medications because they are absorbed directly into the bloodstream through the skin without going through liver metabolism.
  • a method for predicting the therapeutic effect of a candidate drug on Parkinson's disease is provided using the following [Mathematical Formula 1].
  • I k agg is the fluorescence intensity of individual alpha-synuclein aggregates in the drug-treated group
  • C total is the total number of cells in the drug treatment group
  • BA k agg is the area of individual alpha-synuclein aggregates in the untreated group
  • BI k agg is the fluorescence intensity of individual alpha-synuclein aggregates in the drug-untreated group
  • BC total refers to the total number of cells in the untreated group.
  • the candidate drug may be a pyruvate dehydrogenase kinase (PDK) inhibitor.
  • PDK pyruvate dehydrogenase kinase
  • the PDK inhibitor may be at least one selected from the group consisting of GSK2334470 (CAS no. 1227911-45-6), MP7 (CAS no. 1001409-50-2), and OSU03012 (CAS no. 742112-33-0).
  • the GSK2334470 (CAS no. 1227911-45-6) may be a compound of the following chemical formula 1.
  • the MP7 (CAS no. 1001409-50-2) may be a compound of the following chemical formula 2.
  • TH primary antibody
  • pS129-a-syn secondary antibodies conjugated to fluorescent dyes were used to stain, and magnified images were obtained to determine the degree of progression of pathogenic ⁇ -syn aggregate lesions in the brain region where dopaminergic neurons are distributed.
  • PDK inhibitors The inhibitory effect of PDK inhibitors on alpha-synuclein aggregation was evaluated using a dopaminergic cell line (SH-SY5Y) in which the ⁇ -syn-Cry2PHR coding sequence was knocked-in into the AAVS1 locus, and a schematic diagram is shown in Fig. 2B.
  • ⁇ -synuclein comprehensive aggregation score ( ⁇ -CAS) based on these values, which is shown in Fig. 2C.
  • the inhibitory effects of the PDK inhibitor GSK2334470 on alpha-synuclein aggregation and dopaminergic neuron-specific cell death were evaluated using Parkinson's disease patient induced pluripotent stem cell-derived midbrain dopaminergic neurons (PD hiPSC-derived mDA neurons) in which the alpha-syn-mCherry-Cry2clust coding sequence was knocked-in into the AAVS1 locus, and the schematic diagram is shown in Fig. 4A.
  • Fig. 4B it was confirmed that the formation of pathogenic alpha-synuclein aggregates in midbrain dopaminergic neurons stained with TH was inhibited by treatment with the PDK inhibitor GSK2334470.
  • the control group, AAVS1::mCherry-Cry2clust PD hiPSC-derived mDA neurons showed an ⁇ -CAS value of 0.00, confirming that ⁇ -syn aggregation did not occur.
  • GSK2334470 also exhibits inhibitory effects on pathogenic alpha-synuclein aggregation in Parkinson's disease patient-derived induced pluripotent stem cell-derived midbrain dopaminergic neurons.
  • Fig. 4D we confirmed that TH-stained midbrain dopaminergic neuron-specific cell death due to blue light-induced pathogenic alpha-synuclein aggregation was inhibited by treatment with the PDK inhibitor GSK2334470.
  • Fig. 4E the results of quantitative analysis are shown in a graph, and when the ratio of TH-stained midbrain dopaminergic neurons in the control AAVS1::mCherry-Cry2clust PD hiPSC-derived mDA neurons cultured under dark conditions is set as 100%, it was confirmed that the ratio showed a statistically insignificant difference in the control group due to blue light irradiation.
  • GSK2334470 also inhibits apoptosis of Parkinson's disease patient-derived induced pluripotent stem cell-specific midbrain dopaminergic neurons caused by blue light-induced pathological alpha-synuclein aggregation.
  • GSK2334470 has significant activity in inhibiting pathogenic alpha-synuclein aggregate lesions in an animal model of Parkinson's disease.
  • Quantitative data are expressed as mean ⁇ standard deviation and were analyzed using two-way ANOVA, followed by Sidak's post hoc test (** P ⁇ 0.01. **** P ⁇ 0.0001. ns indicates
  • the ⁇ -syn-PFF/ AAV- ⁇ -syn complex injection group showed an increase in the completion time in the pole test and a significant decrease in the performance duration in the rota-rod test compared to the PBS/ AAV-GFP injection control group, confirming that stereotaxic injection of ⁇ -syn-PFF/ AAV- ⁇ -syn into the substantia nigra region of the midbrain induced bradykinesia and motor coordination abnormalities.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter la maladie de Parkinson, contenant un inhibiteur de pyruvate déshydrogénase kinase (PDK) en tant que principe actif, une préparation pharmaceutique la contenant, pour prévenir ou traiter la maladie de Parkinson, ainsi qu'une méthode prédiction de l'effet thérapeutique d'un médicament candidat sur la maladie de Parkinson, permettant de s'attendre à la sélection d'un médicament candidat traitant la maladie de Parkinson et doté d'un effet thérapeutique optimal.
PCT/KR2024/096275 2023-10-10 2024-10-10 Composition pharmaceutique pour prévenir ou traiter la maladie de parkinson, contenant un inhibiteur de pdk en tant que principe actif Pending WO2025080080A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2023-0134273 2023-10-10
KR20230134273 2023-10-10
KR1020240137404A KR20250051596A (ko) 2023-10-10 2024-10-10 Pdk 억제제를 유효성분으로 포함하는, 파킨슨병의 예방 또는 치료용 약학적 조성물
KR10-2024-0137404 2024-10-10

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WO2025080080A1 true WO2025080080A1 (fr) 2025-04-17

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170010947A (ko) * 2015-07-20 2017-02-02 동국대학교 산학협력단 멜라닌 응집 호르몬을 유효성분으로 포함하는 파킨슨병 치료 및 레보도파 부작용 억제용 약학 조성물
KR20210041755A (ko) * 2019-10-08 2021-04-16 성균관대학교산학협력단 단백질 응집체 저해제
KR20210079213A (ko) * 2019-12-19 2021-06-29 주식회사 스탠다임 시누클레인병증 치료용 조성물
WO2021191455A1 (fr) * 2020-03-27 2021-09-30 Universite De Paris Nouvelles cibles thérapeutiques à effet anti-inflammatoire et anti-interféron
KR20220016376A (ko) * 2020-07-31 2022-02-09 부산대학교 산학협력단 신경염증질환 예방 또는 치료용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170010947A (ko) * 2015-07-20 2017-02-02 동국대학교 산학협력단 멜라닌 응집 호르몬을 유효성분으로 포함하는 파킨슨병 치료 및 레보도파 부작용 억제용 약학 조성물
KR20210041755A (ko) * 2019-10-08 2021-04-16 성균관대학교산학협력단 단백질 응집체 저해제
KR20210079213A (ko) * 2019-12-19 2021-06-29 주식회사 스탠다임 시누클레인병증 치료용 조성물
WO2021191455A1 (fr) * 2020-03-27 2021-09-30 Universite De Paris Nouvelles cibles thérapeutiques à effet anti-inflammatoire et anti-interféron
KR20220016376A (ko) * 2020-07-31 2022-02-09 부산대학교 산학협력단 신경염증질환 예방 또는 치료용 조성물

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