WO2012014993A1 - Agent destiné à augmenter le facteur d'initiation de traduction ou le facteur d'élongation de traduction et usages médicaux dudit agent - Google Patents

Agent destiné à augmenter le facteur d'initiation de traduction ou le facteur d'élongation de traduction et usages médicaux dudit agent Download PDF

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WO2012014993A1
WO2012014993A1 PCT/JP2011/067315 JP2011067315W WO2012014993A1 WO 2012014993 A1 WO2012014993 A1 WO 2012014993A1 JP 2011067315 W JP2011067315 W JP 2011067315W WO 2012014993 A1 WO2012014993 A1 WO 2012014993A1
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diseases
translation
factor
translation initiation
disease
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謙二 橋本
環 石間
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国立大学法人 千葉大学
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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
    • A61K31/435—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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention prevents and / or prevents various diseases such as psychiatric diseases, neurological diseases, cerebrovascular diseases, cardiovascular diseases, respiratory diseases, endocrine diseases, metabolic diseases, blood diseases, immune diseases, infectious diseases, and malignant tumors. It relates to a medicament for treatment. More specifically, the present invention relates to a pharmaceutical preparation containing a compound that increases a translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof.
  • Drug treatment is indispensable for the treatment of mental disorders such as depression and schizophrenia, such as antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin / norepinephrine reuptake inhibitors, etc.) ) And antipsychotic drugs (phenothiazine compounds, butyrophenone compounds, benzamide compounds, iminodibenzyl compounds, thiepine compounds, indole compounds, serotonin / dopamine receptor blockers, etc.).
  • antidepressants tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin / norepinephrine reuptake inhibitors, etc.
  • antipsychotic drugs phenothiazine compounds, butyrophenone compounds, benzamide compounds, iminodibenzyl compounds, thiepine compounds, indole compounds, serotonin / dopamine receptor blockers, etc.
  • tetracycline antibiotics are a general term for a group of broad-spectrum antibiotics, and are inexpensively prescribed for Chlamydia infection, rickettsia infection, mycoplasma infection, brucellosis, and spirochete infection (syphilis / Lyme disease). It is a drug.
  • Minocycline one of the tetracycline antibiotics
  • various actions such as neuroprotective action and anti-inflammatory action in addition to its action as an antibiotic.
  • Therapeutic effects on various diseases such as autoimmune diseases and human immunodeficiency virus (HIV) infection have been reported (Non-Patent Documents 1 to 7).
  • the inventors have reported that the second generation antibiotic minocycline or the antiplatelet drug cilostazol has an improving effect in studies such as model animals of schizophrenia and neuroplasticity using cell culture tests.
  • minocycline has an effect of improving cognitive dysfunction caused by administration of the NMDA receptor antagonist phencyclidine and prepulse depressive disorder caused by administration of the NMDA receptor antagonist MK-801 (Non-patent Documents 8 and 9). Furthermore, from a placebo-controlled double-blind study, it has been reported that minocycline significantly improves negative symptoms and cognitive impairment in schizophrenic patients (Non-patent Document 10). In addition, it has been reported that minocycline has an action to improve depressive symptoms in patients with bipolar disorder (Non-patent Document 11).
  • Non-patent Documents 12 and 13 the mechanism of action of minocycline and cilostazol is unclear.
  • PC12 cells which are pheochromocytomas derived from rat adrenal medulla, extend dendrites like nerves by the action of nerve growth factor (Nerve Growth Factor; NGF). Widely used. NGF-induced neurite outgrowth is an experimental system widely used as a treatment mechanism for various diseases (Non-Patent Documents 14 and 15).
  • the regulation of protein expression is closely related to cell growth and cell cycle progression. Therefore, it is expected that abnormalities in the translation process are related not only to the etiology / pathology of human diseases but also to the action of therapeutic agents.
  • Translation of mRNA consists of stages such as initiation, elongation and termination, and many eukaryotic translation initiation factors (eIFs) act specifically at the initiation stage. .
  • the translation initiation factor is also referred to as a polypeptide chain initiation factor, and is a protein group (eIF1, eIF2, eIF3, eIF4, eIF5, etc.) in which a liposome binds amino acids according to the base sequence of mRNA, that is, a translation process of protein synthesis.
  • the final purpose of initiating eIFs and translation is to form the 80S ribosome and place the mRNA start codon, Met-tRNA, on the ribosome P site (peptidyl tRNA binding site).
  • the translation elongation factor is also referred to as a polypeptide chain elongation factor, and is a protein group (eEF1, eEF2, eEF3, eEF4, eEF5, etc.) necessary for the translation process of polypeptide chain elongation that biosynthesizes a protein from mRNA.
  • Translation elongation factors are broadly divided into two types, functionally binding aminoacyl-tRNAs corresponding to the mRNA code to the A-site (aminoacyl-tRNA binding site) of the ribosome and present at the A-site immediately after peptidyl bond formation. It is a factor that translocates peptidyl tRNA to P site. Regulation of translation initiation factor and translation elongation factor is an important process in the sense that it regulates the expression level of the final protein, and changes in mRNA translation initiation and translation elongation control cause diseases in mammals including humans Understanding the control of the translation process is not only to elucidate the causes of various diseases, but also to develop new preventives, diagnostics, and therapeutics. It can be applied.
  • DomercqM Matute C. (2004). Neuroprotection by tetracyclines. Trends Pharmacol Sci 25l: 609-612. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. (2004). The promise ofminocycline in neurology. Lancet Neurol 3: 744-751. Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M. (2004). Clinical potential ofminocycline for neurodegenerative disorders. Neurobiol Dis 217: 359-366. Zemke D, Majid A. (2004). The potential of minocycline for neuroprotection in humanneurologic diseases. Neurobiol Dis 217: 359-366. MiyaokaT. (2008).
  • Noble W Garwood CJ, JHanger DP.
  • OrsucciD Calsolaro V, Mancuso M, Siciliano G. (2009) .2009Neuroprotective effects oftetracyclines: molecular targets, animal models and human disease.
  • the subject of this invention is providing the pharmaceutical formulation effective in various diseases, especially a neurological disease.
  • the present inventors have conducted intensive studies to solve the above problems, and that minocycline or cilostazol has an action of significantly enhancing the NGF-induced neurite outgrowth action in PC12 cells (referred to as neurite outgrowth enhancement action).
  • minocycline or cilostazol has an action of significantly enhancing the NGF-induced neurite outgrowth action in PC12 cells (referred to as neurite outgrowth enhancement action).
  • Tecycline another second-generation antibiotic, has not been effective.
  • the main effect of cilostazol is phosphodiesterase (PDE) 3 inhibitory action, but the other PDE3 inhibitor cilostamide did not show NGF-induced neurite outgrowth effect. May not be related to the PDE3 inhibitory action of cilostazol.
  • the present inventors proceeded to elucidate the mechanism of action of minocycline or cilostazol on enhancing the NGF-induced neurite outgrowth, and the increase of translation initiation factor (eIF4A1 etc.) or translation elongation factor (eEF1A1 etc.) was involved in the action, respectively. It was found for the first time that the present invention was completed.
  • the present invention relates to a pharmaceutical preparation containing a compound having an action of increasing a translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to therapeutic agents for various diseases in which abnormalities of translation initiation factors or translation elongation factors are involved, and further to pharmaceutical formulations effective for neurological diseases.
  • the present invention relates to 1) a neurite outgrowth enhancer containing minocycline and / or cilostazol.
  • the present invention also relates to a neurite elongation enhancer characterized by increasing 2) a translation initiation factor and / or a translation elongation factor.
  • the present invention also relates to a neurite elongation enhancer characterized by increasing eIF4A isoform that is a translation initiation factor and / or eEF1A isoform that is a translation elongation factor.
  • the present invention also relates to 6) a translation initiation factor increasing agent and / or a translation elongation factor increasing agent comprising minocycline and / or cilostazol. Further, it relates to an agent for increasing 7) translation initiation factor eIF4A1 containing minocycline. Furthermore, it relates to an agent for increasing translation elongation factor eEF1A1 containing 8) cilostazol.
  • the present invention also relates to 9) a preventive and / or therapeutic agent for a disease caused by an abnormality in a translation initiation factor and / or translation elongation factor, containing minocycline and / or cilostazol.
  • Psychiatric diseases neurological diseases, cerebrovascular diseases, cardiovascular diseases derived from a decrease in eIF4A isoform which is a translation initiation factor and / or eEF1A isoform which is a translation elongation factor, containing minocycline and / or cilostazol.
  • an agent for preventing and / or treating a disease exhibiting one or more symptoms selected from the group consisting of endocrine diseases, metabolic diseases, blood diseases, immune diseases, infectious diseases, and malignant tumors are examples of a preventive and / or therapeutic agent for a disease exhibiting one or more symptoms selected from the group consisting of respiratory diseases, endocrine diseases, metabolic diseases, blood diseases, immune diseases, infectious diseases, and malignant tumors.
  • minocycline or cilostazol, or a pharmaceutically acceptable salt thereof significantly increased translation initiation factor (eIF4A1) or translation elongation factor (eEF1A1), respectively, compounds that increase translation initiation factor or translation elongation factor are It is effective for various diseases, diseases associated with abnormalities of translation initiation factors or translation elongation factors, and effective for the prevention and / or treatment thereof.
  • various diseases in which abnormalities of translation initiation factors or translation elongation factors have been pointed out and diseases associated with abnormal protein formation such as mental diseases, neurological diseases, cerebrovascular diseases, cardiovascular diseases, respiratory organs It is effective for the prevention and / or treatment of various diseases such as diseases, endocrine diseases, metabolic diseases, blood diseases, immune diseases, infectious diseases, and malignant tumors.
  • FIG. 1 shows the effect of minocycline on nerve growth factor-induced neurite action.
  • Minocycline significantly enhanced NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner, whereas other antibiotic tetracyclines did not affect the effect.
  • FIG. 2 is a diagram showing intracellular expression levels of eIF4A1 protein treated with minocycline and tetracycline. Minocycline significantly increased eIF4A1 protein expression.
  • FIG. 3 is a diagram showing the effect of siRNA treatment and the like on the increase in the expression level of intracellular translation initiation factor eIF4A1 protein of minocycline. The eIF4A1 siRNA treatment significantly decreased the protein expression level of eIF4A1. Negative RNA had no effect.
  • FIG. 1 shows the effect of minocycline on nerve growth factor-induced neurite action.
  • Minocycline significantly enhanced NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner, whereas other antibiotic tetracyclines
  • FIG. 4 shows the effect of eIF4A1 on the NGF-induced neurite outgrowth action of minocycline.
  • FIG. 5 shows the effect of cilostazol on the NGF-induced neurite outgrowth action. Cilostazol significantly enhanced NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner, whereas the other PDE3 inhibitor cilostamide did not affect the effect.
  • FIG. 6 is a graph showing the intracellular expression level of eEF1A1 protein treated with cilostazol and cilostamide.
  • FIG. 7 is a diagram showing the influence of siRNA treatment or the like on the increase in the expression level of cilostazol translation initiation factor eEF1A1 protein in cells.
  • the eEF1A1 siRNA treatment significantly decreased the protein expression level of eEF1A1.
  • Negative RNA had no effect.
  • FIG. 8 is a graph showing the effect of eIF1A1 on the NGF-induced neurite outgrowth action of cilostazol. Under the conditions shown in FIG. 7, when the protein expression level of the translation initiation factor eEF1A1 was decreased by siRNA treatment, the NGF-induced neurite outgrowth action of cilostazol was suppressed.
  • FIG. 7 is a diagram showing the influence of siRNA treatment or the like on the increase in the expression level of cilostazol translation initiation factor eEF1A1 protein in cells.
  • the eEF1A1 siRNA treatment significantly decreased the protein expression level of eEF1A1.
  • Negative RNA had no effect.
  • FIG. 9 shows the effects of tetracycline and minocycline on eEF1A1 protein expression, and the effects of cilostamide and cilostazol on eIF4A1 protein expression.
  • Tetracycline and minocycline did not affect eEF1A1 protein expression, and cilostamide and cilostazol did not affect eIF4A1 protein expression.
  • FIG. 10 is a diagram showing the nucleotide sequence of siRNA of eIF4A1 as an antisense.
  • FIG. 11 is a diagram showing the nucleotide sequence of eEF1A1 siRNA as antisense.
  • the translation initiation factor is a protein group that initiates the process of ribosome binding amino acids according to the base sequence of mRNA, that is, the translation process of protein synthesis.
  • Translation elongation factors are a group of proteins that control the process involved in peptide chain elongation, which advances the translation process of protein synthesis from mRNA.
  • a protein called eIF4A is known to have several isoforms (or subclasses) such as eIF4A1, eIF4A2, and eIF4A3, their functions are considered to be the same, and the effects of the present invention can be achieved.
  • the invention can be implemented for one or more isoforms.
  • eIF4A isoforms.
  • eIF4A1 can be mentioned.
  • the protein called eEF1A among the translation elongation factors is known to have several isoforms (or subclasses) such as eEF1A1, eEF1A2, and eEF1A3, and their functions are considered to be the same.
  • the invention can be implemented for one or more isoforms.
  • these proteins are referred to, they are referred to as eEF1A isoforms.
  • eEF1A1 can be mentioned as a preferred eEF1A isoform.
  • the neurite outgrowth action refers to the action of causing neurite formation in nerve cells, and the enhancement action (neurite outgrowth enhancement action) is, for example, the effect of performing a quantification test as described in the Examples. Can be determined.
  • a compound having a neurite outgrowth enhancing action and having the effect sufficient as a medicine is called a neurite outgrowth enhancer.
  • the present invention relates to a neurite elongation enhancer characterized by increasing a translation initiation factor and / or a translation elongation factor. More preferably, the present invention relates to a neurite extension enhancer characterized by increasing eIF4A isoform which is a translation initiation factor and / or eEF1A isoform which is a translation elongation factor. More preferably, the present invention relates to a neurite outgrowth enhancer characterized by increasing eIF4A which is a translation initiation factor and / or eEF1A which is a translation elongation factor.
  • Minocycline can be used as an enhancer of a translation initiation factor, preferably an eIF4A isoform, more preferably eIF4A1. It can be used as an increaser for cilostazol, a translation elongation factor, preferably an eEF1A isoform, more preferably eEF1A1.
  • the pharmaceutical preparation of the present invention containing a compound that increases a translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof, such as a prophylactic agent and / or therapeutic agent, is administered orally or parenterally.
  • a pharmaceutically acceptable salt thereof such as a prophylactic agent and / or therapeutic agent
  • parenteral administration may be performed by rectal administration using suppositories, transdermal administration using patches, liniments, gels, etc., transmucosal administration using sprays, aerosols, etc. It may be administered internally, intramuscularly, subcutaneously or intraventricularly.
  • the compound that increases the translation initiation factor or translation elongation factor can be used in the form of both a free base or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is preferably a pharmaceutically acceptable acid addition salt, more preferably a hydrochloride.
  • the preventive agent and / or therapeutic agent of the present invention may contain other medicinal ingredients in addition to a compound that increases a translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof.
  • an antioxidant in addition to these medicinal ingredients, an antioxidant, a stabilizer, an antiseptic, a corrigent, a coloring agent, a solubilizer, a solubilizer, a surfactant, an emulsifier, and an antifoaming agent depending on the dosage form as appropriate.
  • suitable physiologically acceptable substances well known to those skilled in the art, such as viscosity modifiers, gelling agents, absorption enhancers, dispersants, excipients, and pH adjusters.
  • the preventive agent and / or therapeutic agent of the present invention is produced by appropriately combining a compound that increases a translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof, and these substances.
  • a compound that increases a translation initiation factor or translation elongation factor or a pharmaceutically acceptable salt thereof, and these substances.
  • the prophylactic and / or therapeutic agent of the present invention is prepared as a preparation for injection (subcutaneous injection, intramuscular injection, or intravenous injection), the form of a solution or suspension is preferred, and for vaginal or rectal administration
  • Semi-solid dosage forms such as creams or suppositories are preferred, and for nasal administration, powder, nasal drops, or aerosol dosage forms are preferred.
  • Injectable preparations can contain, for example, plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol as carriers, and buffers, solubilizers, isotonic agents, and the like can also be added. it can.
  • plasma-derived proteins such as albumin
  • amino acids such as glycine
  • sugars such as mannitol as carriers
  • buffers solubilizers, isotonic agents, and the like can also be added. it can.
  • surfactants such as Tween (trademark) 80 and Tween (trademark) 20, in order to prevent aggregation.
  • parenteral dosage forms other than injectable preparations may contain distilled water or physiological saline, polyalkylene glycols such as polyethylene glycol, oils of plant origin, hydrogenated naphthalene, and the like.
  • preparations for vaginal or rectal administration such as suppositories contain, for example, polyalkylene glycol, petrolatum, cacao oil and the like as common excipients.
  • Vaginal preparations may contain absorption enhancers such as bile salts, ethylenediamine salts, and citrate salts.
  • Inhalation formulations may be solid, may contain, for example, lactose as an excipient, and nasal drops may be water or oil solutions.
  • the exact dose and administration schedule of the preventive agent and / or therapeutic agent of the present invention can be adjusted depending on the required amount, treatment method, disease or degree of necessity for each individual treatment target.
  • the dosage can be determined according to age, weight, general health condition, sex, diet, administration time, administration method, excretion rate, combination of drugs, patient condition, etc. It may be determined in consideration of these factors.
  • a compound that increases translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof, has no problem in pharmacokinetics in humans, and can be used safely.
  • a compound (free base) that increases translation initiation factor or translation elongation factor parenterally, subcutaneously, intravenously, intramuscularly or rectally, depending on the condition, body weight, type of compound, administration route, etc. It is administered at about 0.01 to 1000 mg / person / day, preferably 0.1 to 500 mg / person / day, and orally about 0.01 to 500 mg / person / day, preferably 0.1 to 100 mg. It is desirable to be administered per person / day.
  • the present invention relates to a method for enhancing neurite outgrowth, which comprises administering an agent for increasing a translation initiation factor and / or an agent for increasing a translation elongation factor to a subject.
  • the present invention also relates to the use of an agent for increasing translation initiation factor and / or an agent for increasing translation elongation factor in the method for enhancing neurite elongation and the production of neurite elongation enhancer.
  • the present invention relates to a method for preventing and / or treating a mental illness characterized by enhancing neurite outgrowth by administering to a subject an agent for increasing a translation initiation factor and / or an agent for increasing a translation elongation factor.
  • the present invention also relates to the use of an agent for increasing a translation initiation factor and / or an agent for increasing a translation elongation factor in the production of a method for preventing and / or treating mental illness and a prophylactic and / or therapeutic agent for mental illness.
  • morphometric analysis was performed using digital images of live cells taken with a phase contrast inverted microscope equipped with a camera. . Three fields of view were taken per well. The average number of cells per field was 100. The number of differentiated cells in each visual field was counted by visual recognition. Only cells having one or more neurites with a length equal to the cell body diameter were counted and expressed as a percentage of the total number of cells in the field of view. Measurements were performed blind.
  • Rabbit anti-eIF4A antibody (Abcam) and mouse anti- ⁇ -actin antibody (Sigma Aldrich) diluted at 1: 250 and 1: 10000 in the blocking buffer were used as primary antibodies.
  • an anti-rabbit IgG horseradish peroxidase labeled antibody (GE Healthcare) diluted 25,000 times in TBST containing 5% skim milk and an anti-mouse IgG horseradish peroxidase labeled antibody (GE Health) diluted 25000 times in TBST containing 5% skim milk. Care) was used as the secondary antibody.
  • Antigen proteins on the membrane were detected with ECL TM Plus Western Blotting Detection System (GE Healthcare).
  • PC12 cells were cultured and transfected with the above siRNA using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) and OPTI-MEM (Invitrogen, Carlsbad, CA, USA). 6 hours later, NGF (2.5 ng / ml), and further exchange with DMEM medium containing 0.5% FBA, 1% penicillin / streptomycin with or without the addition of various drugs, to examine the neurite outgrowth enhancing effect And subjected to Western blot analysis. (5) Statistical analysis Data are shown as mean ⁇ standard deviation. Statistical analysis was performed using one-way analysis of variance and post-hoc Bonferroni test. A p value of 0.05 or less was considered statistically significant.
  • siRNA Minocycline or cilostazol significantly increased eIF4A1 or eEF1A1 in PC12 cells, respectively, and when gene was knocked down by the respective siRNA, an increase in eIF4A1 or eEF1A1 in PC12 cells was seen There wasn't. Furthermore, even if siRNA (negative RNA) that had nothing to do with the target was allowed to act, the increase in eIF4A1 or eEF1A1 in PC12 cells was not affected (FIGS. 3 and 7).
  • minocycline or cilostazol significantly increased the number of PC12 cells that showed neurite outgrowth by (2.5 ng / mL) in a concentration-dependent manner, but neurite outgrowth when the gene was knocked down by siRNA treatment Did not increase the number of cells that showed. Furthermore, even when siRNA (negative RNA) that had nothing to do with the target was allowed to act, the increase in the number of cells showing neurite outgrowth was not affected (FIGS. 4 and 8). On the other hand, tetracycline or minocycline did not affect the amount of eEF1A1 protein (FIG. 9). Moreover, cilostamide or cilostazol did not affect the amount of eIF4A1 protein (FIG. 9).
  • minocycline or cilostazol showed a significant enhancing action in the NGF-induced neurite elongation action model, and that the translation initiation factor or translation elongation factor was involved in the enhancement action. It will be appreciated that compounds that increase translation elongation factors will be useful as new therapeutic agents in the future.
  • a compound of the present invention containing a compound that increases a translation initiation factor or translation elongation factor, or a pharmaceutically acceptable salt thereof is used in mental diseases, neurological diseases, cerebrovascular diseases, cardiovascular diseases, respiratory organs It is effective as a prophylactic and / or therapeutic agent for various diseases including diseases, endocrine diseases, metabolic diseases, blood diseases, immune diseases, infectious diseases, and malignant tumors.
  • minocycline and / or cilostazol can be used as neurite outgrowth enhancers.
  • a neurite outgrowth enhancer is accompanied by a specific increase in translation initiation factors, particularly eIF4A1, in minocycline, and a specific increase in translation elongation factors, particularly eEF1A1, in cilostazol. It was a thing. Furthermore, from these, it is possible to use minocycline as a translation initiation factor increasing agent, particularly eIF4A1 increasing agent, and cilostazol as a translation elongation factor increasing agent, particularly eEF1A1 increasing agent. It was.
  • minocycline and / or cilostazol can be used as a preventive and / or therapeutic agent for various diseases caused by abnormal translation initiation factors and / or translation elongation factors, particularly neurological diseases.
  • the compound that increases the translation initiation factor or translation elongation factor of the present invention is a mental disease, neurological disease, cerebrovascular disease, cardiovascular disease, respiratory disease, endocrine disease, metabolic disease. It can be used as a novel pharmaceutical effective for various diseases such as blood diseases, immune diseases, infectious diseases, and malignant tumors.
  • SEQ ID NO: 1 designed oligonucleotide.
  • SEQ ID NO: 2 designed oligonucleotide.
  • SEQ ID NO: 3 Designed oligonucleotide.
  • SEQ ID NO: 4 Designed oligonucleotide.
  • SEQ ID NO: 5 designed oligonucleotide.
  • SEQ ID NO: 6 designed oligonucleotide.
  • SEQ ID NO: 7 designed oligonucleotide.
  • SEQ ID NO: 8 designed oligonucleotide.
  • SEQ ID NO: 9 designed oligonucleotide.
  • SEQ ID NO: 10 designed oligonucleotide.
  • SEQ ID NO: 11 designed oligonucleotide.
  • SEQ ID NO: 12 designed oligonucleotide.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
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  • Endocrinology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation pharmaceutique destinée à prévenir et/ou traiter diverses maladies, contenant un composé apte à augmenter un facteur d'initiation de traduction ou un facteur d'élongation de traduction, ou un sel pharmaceutiquement acceptable de celui-ci, comme principe actif. Selon l'invention, il a été établi pour la première fois que l'augmentation d'un facteur d'initiation de traduction (eIF4A1, par exemple) ou d'un facteur d'élongation de traduction (eEF1A1, par exemple) était impliqué dans l'activité de potentialisation d'élongation de neurite induite par le NGF de la minocycline ou du cilostazol.
PCT/JP2011/067315 2010-07-29 2011-07-28 Agent destiné à augmenter le facteur d'initiation de traduction ou le facteur d'élongation de traduction et usages médicaux dudit agent WO2012014993A1 (fr)

Priority Applications (1)

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JP2012526556A JPWO2012014993A1 (ja) 2010-07-29 2011-07-28 翻訳開始因子または翻訳伸長因子の増加剤、およびその医薬用途

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JP2010170965 2010-07-29
JP2010-170965 2010-07-29

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WO2012014993A1 true WO2012014993A1 (fr) 2012-02-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9227956B2 (en) 2013-04-17 2016-01-05 Pfizer Inc. Substituted amide compounds

Citations (2)

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WO2006082390A1 (fr) * 2005-02-01 2006-08-10 The University Court Of The University Of Glasgow Materiels et methodes de diagnostic et de traitement du syndrome de fatigue chronique
JP2008273953A (ja) * 2007-03-30 2008-11-13 Chiba Univ シロスタゾールの統合失調症治療剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9227956B2 (en) 2013-04-17 2016-01-05 Pfizer Inc. Substituted amide compounds

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