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WO2024195858A1 - Médicament prophylactique/médicament thérapeutique pour paralysie supranucléaire progressive - Google Patents

Médicament prophylactique/médicament thérapeutique pour paralysie supranucléaire progressive Download PDF

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WO2024195858A1
WO2024195858A1 PCT/JP2024/011319 JP2024011319W WO2024195858A1 WO 2024195858 A1 WO2024195858 A1 WO 2024195858A1 JP 2024011319 W JP2024011319 W JP 2024011319W WO 2024195858 A1 WO2024195858 A1 WO 2024195858A1
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psp
gadd34
drug
inhibitor
present
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PCT/JP2024/011319
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English (en)
Japanese (ja)
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治久 井上
恵子 今村
恭理 石塚
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大正製薬株式会社
国立大学法人京都大学
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Publication of WO2024195858A1 publication Critical patent/WO2024195858A1/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
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • 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
    • 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
    • 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 relates to a preventive and/or therapeutic agent for progressive supranuclear palsy (hereinafter, sometimes referred to as PSP). More specifically, the present invention relates to a preventive and/or therapeutic agent for neurodegenerative diseases including PSP, which contains as an active ingredient a growth arrest and DNA damage-inducible protein 34 (hereinafter, sometimes referred to as GADD34; also known as protein phosphatase 1 regulatory subunit 15A; hereinafter, sometimes referred to as PPP1R15A, and GADD34 and PPP1R15A may be referred to together) inhibitor, such as guanabenz.
  • PSP preventive and/or therapeutic agent for progressive supranuclear palsy
  • PSP a preventive and/or therapeutic agent for neurodegenerative diseases including PSP, which contains as an active ingredient a growth arrest and DNA damage-inducible protein 34 (hereinafter, sometimes referred to as GADD34; also known as protein phosphatase 1 regulatory subunit 15A; hereinafter,
  • PSP is a late-onset neurodegenerative disease clinically characterized by postural instability, supranuclear gaze palsy, parkinsonism, and mild dementia (Non-Patent Documents 1-3). Gait disturbance and other symptoms gradually progress, and patients become bedridden on average 4 to 5 years after onset. The prevalence of PSP in Japan is approximately 5 to 17 people per 100,000. PSP is clinically heterogeneous and is classified into classical PSP-Richardson syndrome (PSP-RS), PSP-parkinsonism (PSP-P), PSP-pure akinesia with gait freezing (PSP-PAGF), etc. (Non-patent Document 4). The histopathological hallmarks of PSP are the accumulation of tau and loss of neurons in various brain regions, including dopaminergic neurons in the ventral midbrain, with tau aggregates called globular neurofibrillary tangles observed in the remaining neurons.
  • PSP-RS PSP-Richardson syndrome
  • PSP-P PSP-parkinsonism
  • Parkinson's disease medications and antidepressants are used as symptomatic treatments.
  • the effects are temporary, and as the disease progresses, the therapeutic effect disappears.
  • PERK acts by phosphorylating the substrate, a constitutive subunit (eIF2 ⁇ ) of eukariotic initiation factor 2 (eIF2).
  • eIF2 ⁇ constitutive subunit of eukariotic initiation factor 2
  • the activity of eIF2 ⁇ is regulated by dephosphorylation by the constitutive repressor of eIF-2 ⁇ phosphorylation (CReP; also known as protein phosphatase 1 regulatory subunit 15B; hereafter referred to as PPP1R15B, and sometimes referred to together as CReP and PPP1R15B) or GADD34.
  • CEP constitutive repressor of eIF-2 ⁇ phosphorylation
  • PPP1R15B protein phosphatase 1 regulatory subunit 15B
  • GADD34 GADD34
  • activation of PERK signaling can also be achieved by inhibiting the dephosphorylation of eIF2 ⁇ by inhibiting GADD34.
  • the objective of the present invention is to provide a novel preventive and/or therapeutic agent, or a preventive and/or therapeutic method for PSP.
  • GADD34 inhibitors including the compound represented by the formula [I- 1 ] below (hereinafter, occasionally referred to as "compound [I- 1 ]”), improve the vulnerability and improve cell survival rate of neural cells induced to differentiate from pluripotent stem cells derived from somatic cells of PSP patients, and have completed the present invention based on these new findings.
  • the gist of the present invention is as follows:
  • a preventive and/or therapeutic drug for progressive supranuclear palsy comprising a GADD34 inhibitor as an active ingredient.
  • a GADD34 inhibitor as an active ingredient.
  • the present invention makes it possible to provide an excellent preventive and/or therapeutic agent, or a preventive and/or therapeutic method for PSP, which contains a GADD34 inhibitor as an active ingredient.
  • the cells that are cultured from pluripotent stem cells derived from PSP patients and induced to differentiate into dopamine neurons inherit the genetic background of the patient and can be used as a PSP model.
  • compounds such as guanabenz and salubrinal discovered using the model are considered to have excellent effects on the prevention and/or treatment of PSP.
  • FIG. 1a shows an overview of the experimental design.
  • Figure 1b (top photo) is a photograph showing an immunostained image of the dopaminergic neural progenitor cell marker forkhead box a2 (FOXA2) on day 11 of culture (scale bar: 100 ⁇ m).
  • Figure 1b (middle photo) is a photograph showing an immunostained image of the neuronal marker microtubule-associated protein 2 (MAP2) and the dopaminergic neuronal marker tyrosine hydroxylase (TH) on day 59 of culture (scale bar: 100 ⁇ m).
  • Figure 1b (bottom photo) is a photograph showing an immunostained image of the glial cell marker glial fibrillary acidic protein (GFAP) on day 52 of culture (scale bar: 50 ⁇ m).
  • GFAP glial cell marker glial fibrillary acidic protein
  • Figure 2a is a photograph showing the results of Western blotting of protein kinase R-like endoplasmic reticulum kinase (PERK) protein in ventral midbrain neurons on the 52nd day of culture.
  • PERK protein kinase R-like endoplasmic reticulum kinase
  • Figure 2b shows the quantification of the bands shown in Figure 2a.
  • the bars indicate the mean ⁇ standard deviation.
  • prophylactic and/or therapeutic drug for progressive supranuclear palsy refers to a drug that prevents and/or treats progressive supranuclear palsy (PSP).
  • PSP progressive supranuclear palsy
  • PSP-RS classic PSP-Richardson syndrome
  • PSP-P PSP-parkinsonism
  • PSP-PAGF PSP-pure akinesia with gait freezing
  • GADD34 Growth arrest and DNA damage-inducible protein 34
  • ATF4 activating transcription factor 4
  • PPP1R15A ER stress
  • Inhibition of GADD34 selectively inhibits eIF2 ⁇ phosphatase and improves disorders associated with accumulation of misfolded proteins or impaired proteostasis.
  • disorders associated with accumulation of misfolded proteins or impaired proteostasis include progressive supranuclear palsy (PSP), as well as Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.
  • PERK acts by phosphorylating eIF2 ⁇ as a substrate.
  • the activity of eIF2 ⁇ is regulated by dephosphorylation by CReP (PPP1R15B) or GADD34, and activation of PERK signaling is achieved not only by direct activation of PERK, but also by inhibition of dephosphorylation of eIF2 ⁇ by inhibiting GADD34.
  • inhibiting GADD34 may be effective in cases where compounds targeting PERK itself are ineffective, particularly in patients with PERK SNPs.
  • the GADD34 inhibitor of the present invention does not inhibit CreP (PPP1R15B).
  • GWAS genome-wide association studies
  • the PSP patients to be administered the PSP preventive or therapeutic drug of the present invention are not particularly limited, but are preferably PSP patients accompanied by EIF2AK3 gene polymorphisms (risk SNPs).
  • the GADD34 inhibitor of the present invention can be used in combination with existing preventive and/or therapeutic drugs for PSP or drugs under development that have a mechanism of action other than GADD34 inhibition.
  • existing preventive and/or therapeutic agents for PSP include those used in combination with therapeutic agents for Parkinson's disease or antidepressants, which are used as symptomatic treatments. It is believed that Parkinson's disease medications and antidepressants work by enhancing the release of neurotransmitters from nerve cell terminals. As PSP progresses, the therapeutic effect is no longer observed, possibly due to the loss of targeted nerve cells. Therefore, by preventing neuronal damage and loss with a GADD34 inhibitor in the early stages after the onset of PSP, it may be possible not only to suppress the progression of the disease, but also to maintain the effects of Parkinson's disease medications and antidepressants.
  • the GADD34 inhibitor of the present invention is a substance that inhibits PPP1R15A, and is preferably a substance that selectively inhibits PPP1R15A, and may be effective in combination with a substance that inhibits CReP (PPP1R15B).
  • PPP1R15B CReP
  • this combination inhibits both GADD34 (PPP1R15A) and CReP (PPP1R15B), and may improve disorders associated with the accumulation of misfolded proteins or proteostasis disorders.
  • GADD34 inhibitor refers to the aforementioned compound that inhibits GADD34, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • the inhibitory activity of a "GADD34 inhibitor” against GADD34 can be measured by known methods. For example, see the reference “Boyce, M., et al., Science, 2005, 307(5711), 935-939.” and its “Materials and Methods.”
  • “Guanabenz” is a compound "(E)-1-(2,6-dichlorobenzylideneamino)guanidine” represented by the following formula [I-1], and is known as an ⁇ -2 type adrenergic ⁇ 2 receptor agonist used as a hypertension treatment. As mentioned above, this compound also has a GADD34 inhibitory effect. When the compound is used in the present invention, it may be used in the form of a free compound, a pharma- ceutically acceptable salt thereof, or a solvate of the free compound or a pharma- ceutically acceptable salt thereof.
  • “Salubrinal” is a compound represented by the following formula [I-2], "(2E)-3-phenyl-N-[2,2,2-trichloro-1-[[(8-quinolinylamino)thioxomethyl]amino]ethyl]-2-propenamide”, which is known as a selective inhibitor of the dephosphorylation of eIF2 and specifically inhibits ER stress-induced apoptosis. As mentioned above, this compound also has a GADD34 inhibitory effect. When the compound is used in the present invention, it may be used in the form of a free compound, a pharma- ceutically acceptable salt thereof, or a solvate of the free compound or a pharma- ceutically acceptable salt thereof.
  • the GADD34 inhibitor used in the present invention may be labeled with one or more isotopes, such as 2H , 3H , 13C , 14C , 15N, 17O , 18O, 35S , 18F , 36Cl , 125I , etc.
  • isotopes such as 2H , 3H , 13C , 14C , 15N, 17O , 18O, 35S , 18F , 36Cl , 125I , etc.
  • salt as used herein is not particularly limited as long as it forms a pharma- ceutically acceptable salt with a GADD34 inhibitor, and examples thereof include mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonate salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; acid addition salts such as organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, benzoate, mandelate, ascorbate, lactate, gluconate, malate, fumaric acid, and monosebacic acid; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspart
  • the preferred salt is the hydrochloride, acetate, succinate or maleate, and the more preferred salt is the acetate.
  • the GADD34 inhibitor is the compound represented by the above formula [I-2] (salubrinal)
  • the preferred salt is the hydrochloride or acetate salt
  • the more preferred salt is the hydrochloride salt.
  • solvate includes, for example, hydrates and ethanol solvates.
  • the preferred solvates are hydrates.
  • the "GADD34 inhibitor” in this specification may have an asymmetric center, and in that case, various optical isomers exist. Therefore, the compound as a GADD34 inhibitor, which is an active ingredient of the prophylactic or therapeutic drug for PSP of the present invention (hereinafter, sometimes simply referred to as the compound of the present invention), may exist as separate optically active forms of (R) and (S), and as a racemate or (RS) mixture. In addition, in the case of a compound having two or more asymmetric centers, diastereomers due to each optical isomer also exist.
  • the compound of the present invention includes those containing all of these forms in any ratio.
  • optical isomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry methods well known for this purpose.
  • the compounds of the present invention may have geometric isomers such as cis and trans isomers.
  • the compounds of the present invention include these isomers and those containing these isomers in any ratio.
  • These geometric isomers can also be separated by methods well known to those skilled in the art, and the geometric isomers can be obtained by organic chemistry techniques well known for this purpose.
  • the compounds of the present invention may have stereoisomers, positional isomers, and rotational isomers.
  • the compounds of the present invention include these isomers and those containing these isomers in any ratio.
  • the compound of the present invention may have tautomers, and the compound of the present invention includes these isomers and compounds containing these isomers in any ratio.
  • the inhibitory activity of a GADD34 inhibitor against GADD34 can be measured by known methods. Therefore, a person having ordinary skill in the art to which the present invention pertains can measure the inhibitory activity of any compound against GADD34 by using the above-mentioned publicly known measurement method, and identify a GADD34 inhibitor.
  • a preferred compound is a compound represented by the following formula [I- 1 ] or [I- 2 ], or a pharma- ceutically acceptable salt thereof, or a solvate thereof, and a more preferred compound is a compound represented by the following formula [I- 1 ] (guanabenz), or a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • the GADD34 inhibitors that are the active ingredients of the present invention, including guanabenz, can be commercially available products or products synthesized by known methods.
  • the prophylactic and/or therapeutic agent for PSP of the present invention can be administered orally or parenterally.
  • Preferred administration methods are oral, intravenous or intravenous drip, or transdermal, with oral administration being more preferred.
  • the prophylactic and/or therapeutic agent for PSP of the present invention can be prepared by formulating the above-mentioned GADD34 inhibitor with known carriers, diluents, etc., as appropriate, into an appropriate pharmaceutical composition by a conventional method.
  • oral preparations can be used as tablets, powders, powders, fine granules, granules, liquids, coated tablets, capsules, syrups, jellies, troches, inhalants, etc.
  • parenteral preparations can be used as injections, infusions, transdermal preparations, transmucosal preparations, nasal preparations, enteral preparations, suppositories, patches, etc.
  • Preferred oral dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, jellies, lozenges, inhalants, etc.
  • Preferred parenteral dosage forms include injections, infusions, patches, etc.
  • PSP preventive and/or therapeutic drug of the present invention is in the form of an oral preparation
  • other known additives such as vitamins, amino acids, herbal medicines, natural products, excipients, pH adjusters, cooling agents, suspending agents, thickening agents, solubilizing agents, disintegrants, binders, lubricants, antioxidants, coating agents, colorants, flavoring agents, surfactants, plasticizers, fragrances, stabilizers, etc. may be mixed as necessary within a qualitative and quantitative range that does not impair the effects of the invention.
  • excipients include lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogen phosphate, light anhydrous silicic acid, calcium carbonate, etc.
  • disintegrants include starch, calcium carboxymethylcellulose, etc.
  • binders include starch, polyvinylpyrrolidone, hydroxypropylcellulose, ethylcellulose, carboxymethylcellulose, gum arabic, etc.
  • examples of lubricants include magnesium stearate, talc, hardened oils, etc.
  • stabilizers include lactose, mannitol, maltose, polysorbates, macrogols, polyoxyethylene hardened castor oil, etc.
  • the dosage of the PSP preventive and/or therapeutic agent of the present invention varies depending on the subject, route of administration, target disease, symptoms, etc., but for example, when orally administered to an adult patient with PSP, the single dose is usually 0.1 mg to 1000 mg, preferably 1 mg to 200 mg, of the active ingredient, and it is desirable to administer this amount once to three times a day, preferably before or after meals. When administered parenterally, the single dose is usually 0.01 mg to 100 mg, preferably 0.1 mg to 20 mg, of the active ingredient, and it is desirable to administer this amount once to three times a day.
  • the pharmaceutical of the present invention can be a single preparation (combination drug) or two or more preparations obtained by separately formulating the GADD34 inhibitor and the above-mentioned compound that can be used in combination.
  • the individual preparations can be administered simultaneously or at a certain time interval.
  • the two or more preparations can also be administered at different times a day.
  • the two or more preparations can also be administered by different routes.
  • the medicament of the present invention is formulated as two different types of preparations, it is highly likely that they will be administered simultaneously or at a very short interval. Therefore, it is preferable to state in documents such as package inserts or sales pamphlets of commercially available medicaments that the two drugs are to be used in combination.
  • Prevention means administering the medicament of the present invention to a patient at risk of developing PSP before the onset of the disease.
  • Treatment refers to administering the medicament of the present invention to a patient who has already developed PSP.
  • the treatment includes symptomatic treatment to relieve symptoms resulting from the disease. It also includes treatment to cure or partially cure the disease, and treatment to stop or slow (suppress) the progression of the disease.
  • DMEM Dulbecco's Modified Eagle Medium
  • KSR KnockOut Serum Replacement SB: SB431542
  • SAG Smoothened Agonist Pur: Purmorphamine
  • BDNF Brain-derived neurotrophic factor
  • GDNF Glial cell line-derived neurotrophic factor
  • dbcAMP Dibutyryl cyclic AMP
  • room temperature refers to 20 to 30°C unless otherwise specified.
  • iPS cells were generated according to the method described in Okita, K., et al., Stem Cells, 2013, 31(3), 458-466. or Takahashi, K., et al., Cell, 2007, 131(5), 861-872.
  • the human iPS cells were generated from peripheral blood mononuclear cells (PBMCs) of three PSP patients and two healthy subjects, and from skin fibroblasts of one healthy subject.
  • PBMCs peripheral blood mononuclear cells
  • Genomic DNA was extracted from iPS cells using the Pure Link Genomic DNA mini kit (Thermo Fisher Scientific). The extracted DNA was then amplified by PCR using KOD FX Neo (TOYOBO), and the amplified DNA was purified using MagExtractor (TOYOBO). The DNA was then labeled and purified using BigDye XTerminator Purification Kit (Applied Bioscience), and single nucleotide polymorphisms (SNPs) were determined by Sanger sequencing using an ABI 3500 xl (Applied Bioscience). The results of the SNP analysis are shown in Table 1.
  • Example 3 Preparation of dopaminergic neuron cells derived from iPS cells
  • Dopaminergic neurons were generated from iPS cells by following the method described in the literature "Kriks, S., et al., Nature, 2011, 480(7378), 547-551.”
  • the changes from the above literature are as follows. Tryple Select (Thermo Fisher Scientific) was added to the iPS cell colonies, and they were incubated in a 37°C incubator for 4 minutes, after which they were dissociated into single cells.
  • the dissociated iPS cells were seeded at 40,000 cells/ cm2 on a 96-well plate coated with iMatrix-511.
  • the seeded cells were cultured for 11 days in KnockOut Serum Replacement (KSR) medium containing N2 medium.
  • KSR KnockOut Serum Replacement
  • Dopaminergic neural progenitor cells were obtained using Smoothened agonist (SAG) as a sonic hedgehog (Shh) agonist. From the 11th day, the dopaminergic neural progenitor cells were cultured in Neurobasal medium. On day 20 of culture, cells were dissociated with Accumax (Innovative Cell Technologies) and replated at 300,000 cells/ cm2 onto iMatrix-511-coated 96-well plates for final maturation to obtain a ventral midbrain neuronal population containing dopaminergic neurons. The detailed differentiation induction protocol and the results of differentiation induction are shown in FIG. 1a, FIG. 1b, and FIG. 1c, respectively.
  • Example 4 Western Blotting After harvesting the cultured ventral midbrain neurons described above, they were centrifuged at 200 ⁇ g, and the pellet was dissolved in RIPA buffer (Thermo Fisher Scientific). After sonication, the lysate was centrifuged at 20,000 ⁇ g for 10 min at 4 °C, and the supernatant was used. Protein concentration was determined using a bicinchoninic acid (BCA) assay kit (Thermo Fisher Scientific). 10 ⁇ g of protein was loaded onto a 10% polyacrylamide gel for size separation and transferred to an Immobilon-P membrane (Merck, Darmstadt, Germany). After blocking with 5% BSA, primary antibodies were applied overnight at 4 °C, and secondary antibodies were applied for 1 h at room temperature.
  • BCA bicinchoninic acid
  • Membranes were visualized using an ECL Prime detection kit (GE Healthcare). Images were acquired with an ImageQuant LAS 4000 (GE Healthcare). The following primary antibodies were used in this experiment. ⁇ PERK (1:1,000; 5683; Cell Signaling Technology) and ⁇ -actin (1:20,000; A5441; Merck). The results of Western blotting are shown in Figures 2a and 2b.
  • Example 5 Cell Viability Assay The ventral midbrain neurons were exposed to tunicamycin for 24 hours in a 37°C incubator. To evaluate the effect of ameliorating cell vulnerability, guanabenz or salubrinal were simultaneously treated as GADD34 inhibitors. Cell viability was evaluated using CellTiter 96 Aqueous One Solution (Promega) and calculated based on the absorbance at 490 nm. The results of the cell viability assay are shown in Figures 3a, 3b and 3c.
  • Formulation Example 1 Granules containing the following ingredients are prepared: (Prescription) Ingredients GADD34 inhibitor 10mg Lactose 700mg Cornstarch 274mg HPC-L 16mg 1000mg (Production method) The GADD34 inhibitor and lactose are passed through a 60 mesh sieve. Cornstarch is passed through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropyl cellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated (extrusion granulation, pore size 0.5-1 mm), and then dried. The resulting dried granules are passed through a vibrating sieve (12/60 mesh) to obtain granules.
  • HPC-L low-viscosity hydroxypropyl cellulose
  • Formulation Example 2 A capsule filling powder is prepared containing the following ingredients: Ingredients GADD34 inhibitor 10mg Lactose 79mg Cornstarch 10mg Magnesium stearate 1mg 100mg (Production method) The GADD34 inhibitor and lactose are passed through a 60 mesh sieve. Cornstarch is passed through a 120 mesh sieve. These are mixed with magnesium stearate in a V-type mixer. 100 mg of the 10-fold powder is filled into a No. 5 hard gelatin capsule.
  • Formulation Example 3 Granules for filling capsules are prepared containing the following ingredients: Ingredients GADD34 inhibitor 15mg Lactose 90mg Cornstarch 42mg HPC-L 3mg 150mg (Production method) The GADD34 inhibitor and lactose are passed through a 60 mesh sieve. Cornstarch is passed through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropyl cellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and then dried. The resulting dried granules are sieved through a vibrating sieve (12/60 mesh) and sized, and 150 mg of the granules are filled into a No. 4 hard gelatin capsule.
  • GADD34 inhibitor 15mg Lactose 90mg Cornstarch 42mg HPC-L 3mg 150mg
  • HPC-L low-viscosity hydroxypropyl cellulose
  • Formulation Example 4 A tablet containing the following ingredients is prepared: Ingredients GADD34 inhibitor 10mg Lactose 90mg Microcrystalline cellulose 30mg Magnesium stearate 5mg CMC-Na 15mg 150mg (Production method) The GADD34 inhibitor, lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for formulation. This mixed powder is directly compressed to obtain 150 mg tablets.
  • GADD34 inhibitor 10mg Lactose 90mg Microcrystalline cellulose 30mg
  • Magnesium stearate 5mg CMC-Na 15mg 150mg (Production method) The GADD34 inhibitor, lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain
  • Formulation Example 5 A tablet containing the following ingredients is prepared: Ingredients GADD34 inhibitor 10mg Lactose 90mg Microcrystalline cellulose 30mg Magnesium stearate 5mg 135mg (Production method) The GADD34 inhibitor, lactose, and microcrystalline cellulose are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for formulation. This mixed powder is directly compressed to obtain 135 mg tablets.
  • the pharmaceutical of the present invention which contains a GADD34 inhibitor such as guanabenz as an active ingredient, has excellent effects in the prevention and/or treatment of PSP. Therefore, the present invention makes it possible to provide a pharmaceutical useful for the prevention and/or treatment of PSP, and is expected to contribute to further development of the pharmaceutical industry.

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Abstract

L'invention concerne un nouveau médicament prophylactique et/ou un nouveau médicament thérapeutique utile pour la paralysie supranucléaire progressive (PSP), le médicament prophylactique et/ou le médicament thérapeutique contenant, en guise de principe actif, un inhibiteur de la protéine 34 inductrice d'arrêt de croissance et de dommages à l'ADN (GADD34) comprenant du guanabenz qui est un composé représenté par la formule [I-1].
PCT/JP2024/011319 2023-03-23 2024-03-22 Médicament prophylactique/médicament thérapeutique pour paralysie supranucléaire progressive WO2024195858A1 (fr)

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