WO2018030762A1 - Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk - Google Patents

Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk Download PDF

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WO2018030762A1
WO2018030762A1 PCT/KR2017/008569 KR2017008569W WO2018030762A1 WO 2018030762 A1 WO2018030762 A1 WO 2018030762A1 KR 2017008569 W KR2017008569 W KR 2017008569W WO 2018030762 A1 WO2018030762 A1 WO 2018030762A1
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zinc
thiazol
indol
amino
ylmethylene
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PCT/KR2017/008569
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English (en)
Korean (ko)
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김양희
박황서
고재영
엄재원
김태윤
서보라
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세종대학교산학협력단
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Priority claimed from KR1020170098417A external-priority patent/KR101911785B1/ko
Application filed by 세종대학교산학협력단 filed Critical 세종대학교산학협력단
Priority to EP17839780.8A priority Critical patent/EP3498277B1/fr
Priority to US16/323,963 priority patent/US20190167647A1/en
Priority to ES17839780T priority patent/ES2901059T3/es
Publication of WO2018030762A1 publication Critical patent/WO2018030762A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to a pharmaceutical composition for treating stroke, and more particularly, to a pharmaceutical composition for treating stroke based on AMPK inhibitory function.
  • Stroke is a collective term for local neurological symptoms that are suddenly caused by abnormal brain blood flow.
  • the brain takes up only 2% of its body weight by weight, but the blood flow to the brain is 15% of cardiac output and 20% of the body's oxygen consumption.
  • the brain uses only glucose as an energy source, so necrosis easily occurs even if the energy supply is interrupted for a while. Therefore, abnormalities in cerebral blood flow are closely related to brain damage.
  • Brain damage caused by stroke includes various toxic mechanisms such as excitotoxicity, oxidative stress, apoptosis and zinc neurotoxicity. Excavation is necessary.
  • Korean Patent Laid-Open Publication No. 1283416 discloses a neuroprotective method in which an AMPK inhibitor Compound C or FAS inhibitor C75 is administered to an ischemic mouse to significantly reduce the size of the infarct so that function is preserved after stroke or ischemic injury. .
  • the present invention is to solve various problems, including the above problems, it is an object of the present invention to provide a new stroke treatment based on the AMPK inhibitory function effective for various mechanisms of stroke.
  • these problems are exemplary, and the scope of the present invention is not limited thereby.
  • the present invention provides a pharmaceutical composition for treating stroke, which contains a compound having a structural formula of Formula 1 as an active ingredient:
  • R 1 to R 5 are each independently hydrogen, a hydroxy group, a halogen, a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 7 carbon atoms, an amine group, a carboxyl group or R 2 And R 3 together form a —O— (CH 2 ) n —O— ring or a substituted or unsubstituted benzene ring (n is an integer from 1 to 3), R 6 is hydrogen or a methyl group, and R 7 is hydrogen Or halogen)
  • FIG. 1 is a photograph showing that the neurotoxicity was increased after zinc treatment in cultured cerebral cortical neurons (A) and the degree of cytotoxicity after treatment with Compound C (+ Cpd C), an AMPK inhibitor, through TUNEL staining and LDH assay. Quantified graphs (B and C).
  • FIG. 2 is a Western blot photograph (A) and an enzyme activity assay (B) graph confirming that AMPK activity is increased after zinc treatment in cultured cerebral cortical neurons.
  • FIG. 3 shows Western blot photographs (A) and AMPK inhibitor Compound C (+ Cpd C), which showed increased expression of apoptosis promoting gene and caspase-3 activity after zinc treatment in cultured cerebral cortical neurons.
  • Western blot photograph (B) shows that both increase and caspase-3 activity was decreased.
  • Figure 4 is the purchase of the AMPK activity assay kit (CycLex, Japan) and recombinant AMPK ( ⁇ 2 / ⁇ 1 / ⁇ 1; CycLex, Japan) to measure the enzyme activity and compared to the compound C effect 40 showing a similar or stronger inhibitory effect It is a graph which selected two candidate compounds.
  • FIG. 5 is a graph showing whether various neurotoxic inhibition is observed by inducing various neurotoxicity in cultured cerebral cortical neurons, treating 7 selected compounds and quantifying the degree of cytotoxicity through LDH assay.
  • Figure 6 is a graph comparing the brain damage of the experimental animals and the control animals compared with the control group to observe the brain damage inhibitory effect by administering drug # 28 to the animal model of the stroke.
  • FIG. 7 is a graph showing the results of an acute toxicity test by administering the final selected drug # 28 to rats and extracting spleen (A), liver (B) and kidney (C).
  • FIG. 8 is a graph illustrating a neuroprotective effect by searching for compounds having a structure similar to that of the previously selected drug # 28 and treating 25 similar compounds selected to zinc-induced cerebral cortical neurons.
  • FIG. 9 is a graph illustrating the neuroprotective effect of 12 drugs that showed a significant drug effect on zinc toxicity, and were treated with NMDA-induced neurotoxicity in cerebral cortical neurons.
  • FIG. 10 is a graph illustrating the neuroprotective effect of 12 drugs selected in cerebral cortical neurons of mice induced with neurotoxicity by H 2 O 2 .
  • FIG. 11 is a graph illustrating treatment of # 28 drug and clioquinol of the present invention to neurons by concentration, and analysis of free zinc concentration with a pZn meter.
  • 15 is a photograph of a neuron treated with 4CO1, 4CO7, and # 28 drugs and treated with FluoZin-3 staining material, followed by confocal laser microscopy (A).
  • Figure 16 is a graph of neuronal cells treated with hydrogen peroxide (H 2 O 2 ), zinc chelator TPEN or CaEDTA, calcium chelator ZnEDTA and whether neurotoxin reduction.
  • 17 is a photomicrograph of the toxic inhibitory effect of the drug after treatment with hydrogen peroxide (H 2 O 2 ), TPEN, # 28, 4C01, 4C07 drug to FluoZin-3.
  • FIG. 18 is a graph illustrating whether the iontocarrier is inhibited in toxicity by treating ionomycin and # 28 drugs in concentrations in neurons.
  • 19 is a graph analyzing the chelation effect on calcium treated with Ca 2 + , # 28 drug and EDTA on the test tube and treated with the fluorescent Fura-2 dye.
  • 20 is a graph analyzing the activity of caspase-3 by treating TPEN, zinc, # 28 drug and clioquinol in neurons (A) and neurotoxicity (LDH secretion) (B).
  • FIG. 21 is a graph illustrating the change in the concentration of zinc in neurons by treating neuronal cultures with normal cultures, zinc-added cultures, and zinc-free cultures, treatment with clioquinol and # 28 drugs, and treatment with the fluorescent substance ZinPyr-1. .
  • AMP-activated protein kinase is a heterologous trimer protein consisting of a catalyst ⁇ subunit ( ⁇ 1 or ⁇ 2), and two regulatory subunits ( ⁇ and ⁇ ). AMPK is phosphorylated and activated at low cellular energy levels, and then regulates cell metabolism to restore gene levels over time by regulating gene expression over time. Increasing the AMP / ATP ratio, changing the cell pH and redox state, and increasing the creatine / phosphocreatin ratio are known to activate AMPK.
  • the present invention provides a pharmaceutical composition for treating stroke, which contains a compound having a structural formula of Formula 1 as an active ingredient:
  • R 1 to R 5 are each independently hydrogen, a hydroxy group, a halogen, a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 7 carbon atoms, an amine group or a carboxyl group, or R 2 and R 3 together form a —O— (CH 2 ) n —O— ring or a substituted or unsubstituted benzene ring (n is an integer from 1 to 3), R 6 is hydrogen or a methyl group, and R 7 is Hydrogen or halogen)
  • the substituted alkyl group may be a trifluoromethyl group and the halogen may be iodine, bromine or chlorine.
  • the compound is (5Z) -5- (1H-Indol-3-ylmethylene) -2- ⁇ [2- (trifluoromethyl) phenyl] amino ⁇ -1,3-thiazol-4 (5H) -one, (5Z) -5- (1H-Indol-3-ylmethylene) -2- ⁇ [3- (trifluoromethyl) phenyl] amino ⁇ -1,3-thiazol-4 (5H) -one, ( 5Z) -2-[(3-Bromophenyl) amino] -5- (1H-indol-3-ylmethylene) -1,3-thiazol-4 (5H) -one, (5Z) -5- (1H-Indol- 3-ylmethylene) -2-[(4-methylphenyl) amino] -1,3-thiazol-4 (5H) -one, (5Z) -5- (1H-Indol-3-ylmethylene) -2-[(3 -
  • the stroke may be a hemorrhagic stroke, an ischemic stroke or a metal toxicity stroke, and the metal may be lead, mercury, or manganese. (manganese), arsenic, thallium, iron, iron, zinc, cadmium, bismuth or tin, the ischemic stroke may be excitatory neuronal death or It may be caused by oxidative neuronal death.
  • the effective amount of the compound in the pharmaceutical composition of the present invention may vary depending on the type of affected part of the patient, the site of application, the number of treatments, the treatment time, the dosage form, the condition of the patient, the type of supplement, and the like.
  • the amount used is not particularly limited, but may be 0.01 ⁇ g / kg / day to 10 mg / kg / day.
  • the daily dose may be administered once or in two or three times a day at appropriate intervals or may be administered intermittently at intervals of several days.
  • the compound may be contained at 0.1-100% by weight based on the total weight of the composition.
  • the pharmaceutical compositions of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • the preparation of the pharmaceutical compositions may be used as additives for the preparation of solids or liquids.
  • the additive for preparation may be either organic or inorganic.
  • excipients include lactose, sucrose, white sugar, glucose, cornstarch, starch, talc, sorbet, crystalline cellulose, dextrin, kaolin, calcium carbonate and silicon dioxide.
  • binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, calcium citrate, Dextrin, pectin, and the like.
  • the lubricant include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, and the like.
  • coloring agent if it is normally permitted to add to a pharmaceutical, all can be used. These tablets and granules can be appropriately coated according to sugar, gelatin coating and other needs. Moreover, preservatives, antioxidants, etc. can be added as needed.
  • compositions of the present invention may be prepared in any formulation commonly prepared in the art (e.g., Remington's Pharmaceutical Science, latest edition; Mack Publishing Company, Easton PA), and the form of the formulation is not particularly limited. . These formulations are described in Remington's Pharmaceutical Science, 15 th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania 18042 (Chapter 87: Blaug, Seymour), a prescription generally known for all pharmaceutical chemistries.
  • the compound may be administered orally or parenterally, and preferably, by parenteral administration, intravenous injection, subcutaneous injection, intracerebroventricular injection, intracerebrospinal fluid injection Intramuscular injection, intraperitoneal injection, and the like.
  • the mouse cerebral cortical neurons used in the present invention were extracted and cultured from the brains of mouse embryos and added Dulbecco's modified Eagle's medium (DMEM, Gibco, Grand Island, NY) to which 5% fetal bovine serum (FBS) and 5% horse serum (HS) were added. , US) was incubated at 95% humidity, 5% CO 2 and 37 °C temperature conditions. The cells were grown to a density of 2 ⁇ 10 4 cells in a 24-well tissue culture plate for activation and differentiation of cells and cultured in MEM medium without FBS and HS before treatment with zinc and compounds.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • HS horse serum
  • zinc toxicity is one of the representative causes of stroke, and it was confirmed whether zinc toxicity induced in the cultured cerebral cortical neurons was reduced by AMPK inhibitor treatment.
  • the cultured cerebral cortical neurons according to one embodiment of the present invention treated with 300 ⁇ M of zinc (ZnCl 2 ) for 10 minutes and then removed and cytotoxicity (cytotoxicity) after 10 hours TUNEL staining or LDH (Lactate Dehydrogenase)
  • the cells were treated with AMPK inhibitor Compound C (+ Cpd C, Tocris) at 20 ⁇ M and then neurotoxic reduction was observed.
  • TUNEL staining confirmed that neurotoxicity was increased after zinc treatment in cerebral cortical neurons (Fig. 1A).
  • the cytotoxicity was quantified by TUNEL staining and LDH analysis and treated with Compound C (+ Cpd C), an AMPK inhibitor. It was confirmed that zinc neurotoxicity was significantly reduced (FIGS. 1B and 1C).
  • the AMPK activity was observed by Western blot and enzyme activity analysis after zinc treatment in cortical neurons.
  • the cultured cerebral cortical neurons were treated with 300 ⁇ M of zinc (ZnCl 2 ) for 10 minutes and then removed. After 0.5, 1, 2, 4, and 6 hours, the cell samples were loaded on polyacrylamide gels with protein leather and protein Isolate according to size. The antibody was then processed, washed and read.
  • Example 3 AMPK Inhibition of zinc toxicity through inhibition of activity
  • zinc toxicity was induced by treating cerebral cortical neurons with 300 ⁇ M of zinc (ZnCl 2 ) for 2, 3, 4, 5 and 6 hours.
  • the protein of each sample was isolated and subjected to Western blot, and the relationship between zinc toxicity and apoptosis was confirmed by treatment with Compound C (+ Cpd C), an AMPK inhibitor, at 20 ⁇ M.
  • the primary screening was performed on compounds that may act as AMPK inhibitors.
  • AMPK activity is related to the zinc toxicity mechanism, and other studies have reported an increase in AMPK activity and Bim expression in the excitatory toxicity mechanism.
  • the AMPK enzyme is an enzyme in which three subunits of ⁇ , ⁇ and ⁇ form a complex structure, and the alpha subunit has kinase enzymatic activity.
  • Previous studies have shown that AMPK alpha2 significantly inhibits neurotoxicity caused by ischemia in knock-out mice, unlike alpha1. Therefore, in the present invention, candidate chemicals capable of inhibiting AMPK enzyme activity by targeting alpha2 were selected through structure-based virtual screening, and finally 208 candidate compounds were selected.
  • Example 4-1 The 208 compounds selected in Example 4-1 were obtained from a compound library manufacturer (Interbioscreen, Russia) and subjected to secondary screening through observation of their inhibitory effect on AMPK enzyme activity.
  • AMPK enzyme activity was measured using AMPK activity assay kit (CycLex, Japan) and recombinant AMPK ( ⁇ 2 / ⁇ 1 / ⁇ 1; CycLex, Japan).
  • AMPK activity assay kit CycLex, Japan
  • recombinant AMPK ⁇ 2 / ⁇ 1 / ⁇ 1; CycLex, Japan
  • 40 drugs showed a similar or better inhibitory effect than compound C at 10 ⁇ M.
  • the 40 drugs are shown in Table 1 below.
  • the neuroprotective effect was observed by treating each of the 40 selected drugs with zinc at 12 hr after treating and removing 300 ⁇ M of zinc for 10 minutes to cultured cerebral cortical neurons.
  • the degree of death of the cells was quantified by LDH analysis, and each effect was expressed as an average value, and four separate experiments were performed for each of the selected drugs (FIG. 4).
  • the neurotoxicity model used includes excitatory toxicity, oxidative damage, and apoptosis, which are thought to be the cause of stroke.
  • excitatory toxicity models NMDA was treated, and the oxidative damage model was iron.
  • Toxicity and H 2 O 2 toxicity model was used, and apoptosis model was used as TPEN, staurosporine and etoposide toxicity model.
  • the TPEN is a zinc chelator and is known to induce typical apoptosis in neurons.
  • Storosporin is one of the representative apoptosis inducing enzymes as a kinase inhibitor and etoposide is DNA. It is a drug known to cause cell death due to damage.
  • Compound # 35 and Compound # 28 had an inhibitory effect on all toxicity (FIG. 5).
  • Compound # 28 from the library vendor was (Z) -5-((1H-indol-3-yl) methylene) -2-((3-hydroxyphenyl) amino) thiazol-4 (5H)-having the structure Verified that it is one:
  • Example 5 Inhibitory effect on brain injury in stroke animal model
  • Example 4-4 In order to confirm whether the compound selected as # 28, which was finally selected in Example 4-4, was effective in an animal model, the compound was treated with a stroke model animal that induced brain injury, and then whether the brain damage inhibitory effect was observed was examined. .
  • a permanent model of cerebral artery was constructed using male Sprague-Dawley (SD) rats aged 8-9 weeks. CBF was measured using laser Doppler flowmetry 30 minutes before and after 10 minutes after permanent middle cerebral artery occlusion (MCAO) and is shown in Table 3 below. Subsequently, the final selected AMPK inhibitor candidate compound # 28 (75 ng in 3 ⁇ l) or vehicle (10% DMSO) was 0.8 mm rear and 1.2 mm flank of the brain at 3.8 mm depth 15 minutes after MCAO. Intracerebroventricular injection was performed. After that, the degree of motor deficit of rats was evaluated.
  • the criteria for evaluation indicate that the deficit does not indicate a deficiency . Mild, opposite rotations are classified as moderate and loss of circling or loss of reflexes are classified as severe deficit.
  • the rat model was obtained 24 hours after induction of ischemia in the rat model and stained with 2% 2,3,5-triphenyl tetrazolium chloride (TTC) to measure the degree of cerebral infarction.
  • TTC 2,3,5-triphenyl tetrazolium chloride
  • the final selected compound # 28 was injected into rats and acute toxicity results were observed.
  • SD rats 8-9 week old male Sprague-Dawley (SD) rats were injected intravenously with Compound # 28, the final selected AMPK inhibitor candidate compound, at 75 ⁇ g / kg or vehicle (10% DMSO) per rat. intravenous injection) and repeated four times.
  • Example 7 Detection of similar compounds and observation of zinc toxicity inhibitory effect
  • neurotoxicity models for observing neurotoxicity inhibitory effects include excitotoxicity and oxidative damage, which are classified as a cause of stroke.
  • the excitatory toxicity model is NMDA (N-methyl-D-aspartate).
  • H 2 O 2 hydrogen peroxide
  • NMDA 50 ⁇ M
  • H 2 O 2 100 ⁇ M
  • (10 ⁇ ) and # 28, a previously selected drug, were treated (20 ⁇ ). Since the neurons were stained with propidium iodide (PI), the number of stained cells was quantified to measure the degree of cell death. Cells dead after the staining are stained with PI because of lack of selective permeability of the cell membrane, while healthy cells are not stained.
  • PI propidium iodide
  • the # 28 drug of the present invention was treated with the zinc fluorescent material ZnAF (2.5 ⁇ M) on a test tube by concentration (2.5-20 ⁇ M) and the control group was a very powerful zinc chelator.
  • ZnAF zinc fluorescent material
  • concentration 2.5-20 ⁇ M
  • the control group was a very powerful zinc chelator.
  • clioquinol 1 ⁇ 5 ⁇ M was used and free zinc concentration was measured using a pZn meter (NeuroBioTex Inc).
  • the cortical neurons of the cultured mice were pre-treated with FluoZin-3 staining material and exposed to high concentrations of zinc, followed by 4CO1 (20 ⁇ M) and 4CO7 (20 ⁇ M). And # 28 (20, 50 ⁇ M) drug was used to observe the image using a confocal laser microscope and the fluorescence size was quantitatively measured using a fluorometer.
  • TPEN a zinc chelator that easily enters cells
  • EDTA a zinc chelator that easily enters cells
  • free zinc ions are maintained in the cells, leading to neuronal death.
  • caspase-3 protease activity is decreased during apoptosis.
  • the # 28 drug and clioquinol of the present invention not only acts as a chelator, but also acts as an ion permeable carrier, which is introduced into the cell in combination with zinc and then the zinc is released from the drug because the concentration of free zinc in the cytoplasm is too low. It was expected that the concentration of free zinc was maintained to decrease the neurotoxicity by TPEN, and the activity and neurotoxicity (LDH secretion) of caspase-3 were observed by treatment with zinc, # 28 drug and clioquinol.
  • ZinPyr-1 is a fluorescent dye that has a lower Kd value than FluoZin-3 and is used to measure zinc concentrations at lower concentrations. ZinPyr-1 is used to determine whether the # 28 drug of the present invention can act as an ion permeable carrier. It was. Specifically, after treating ZinPyr-1 to the cultured cerebral cortical neurons, # 28 drug (0.05 ⁇ M) and clioquinol (0.5 ⁇ M) were treated to a commonly used neuronal cell culture and the untreated group was used as a control. The change of zinc ion concentration in neurons was measured.
  • the increase of zinc by clioquinol was observed in normal culture conditions, but the increase by # 28 drug was not clearly observed. Therefore, after adding zinc at a concentration of 0.5 ⁇ M to the cell culture solution, the zinc concentration was observed in the cells. As a result, a significant increase in zinc was observed by treatment with clioquinol and # 28 drug (FIG. 21). Therefore, the # 28 drug of the present invention may also act as an ion permeable carrier and increase zinc to a low level when compared to clioquinol.
  • clioquinol has a high zinc affinity, which can chelate high concentrations of zinc, but it is well known that toxicity can be caused by easily increasing cytoplasmic zinc concentration due to the ion permeability of the drug itself. Therefore, Clioquinol is not suitable as a stroke treatment, but the # 28 drug of the present invention functions as an ion permeable carrier at a level that does not significantly increase the level of cytoplasmic zinc, and if the free zinc in the cytoplasm is increased to a level at which toxicity is induced, clay It is believed that zinc homeostasis is regulated to an appropriate level through nitridation.
  • AMPK enzyme plays an important role in zinc toxicity, which is considered to be one of the causes of stroke, and has been screened several times in a new compound candidate group that inhibits AMPK enzyme activity.

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Abstract

La présente invention concerne une nouvelle composition pour le traitement d'un accident vasculaire cérébral, qui traite l'accident vasculaire cérébral à l'aide d'un nouveau composé inhibant l'activité AMPK dans la neurotoxicité induite par le zinc, qui est une des principales causes des accidents vasculaires cérébraux.
PCT/KR2017/008569 2016-08-09 2017-08-08 Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk WO2018030762A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP17839780.8A EP3498277B1 (fr) 2016-08-09 2017-08-08 Composition pharmaceutique pour un traitement de l'accident vasculaire cérébral basé sur l'inhibition de l'ampk
US16/323,963 US20190167647A1 (en) 2016-08-09 2017-08-08 Pharmaceutical composition for stroke treatment based on ampk inhibition
ES17839780T ES2901059T3 (es) 2016-08-09 2017-08-08 Composición farmacéutica para el tratamiento de apoplejía basado en la inhibición de AMPK

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KR20160101093 2016-08-09
KR10-2016-0101093 2016-08-09
KR1020170098417A KR101911785B1 (ko) 2016-08-09 2017-08-03 Ampk 억제기능에 기반한 뇌졸중 치료용 약학적 조성물
KR10-2017-0098417 2017-08-03

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080056730A (ko) * 2005-09-16 2008-06-23 토렌트 파마슈티칼스 리미티드 티아졸리논과 옥사졸리논 및 이의 ｐｔｐ１ｂ 억제제로서의용도
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
US20140031547A1 (en) * 2010-12-14 2014-01-30 Electrophoretics Limited CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES
CN104059060A (zh) * 2014-05-30 2014-09-24 西安交通大学 一种5-(1h-吲哚-3-亚甲基)-1,3-噻唑烷-4-酮类衍生物及其合成方法和应用
WO2015153959A2 (fr) * 2014-04-04 2015-10-08 The Regents Of The University Of Michigan Petites molécules inhibitrices de mcl-1 et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080056730A (ko) * 2005-09-16 2008-06-23 토렌트 파마슈티칼스 리미티드 티아졸리논과 옥사졸리논 및 이의 ｐｔｐ１ｂ 억제제로서의용도
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
US20140031547A1 (en) * 2010-12-14 2014-01-30 Electrophoretics Limited CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES
WO2015153959A2 (fr) * 2014-04-04 2015-10-08 The Regents Of The University Of Michigan Petites molécules inhibitrices de mcl-1 et leurs utilisations
CN104059060A (zh) * 2014-05-30 2014-09-24 西安交通大学 一种5-(1h-吲哚-3-亚甲基)-1,3-噻唑烷-4-酮类衍生物及其合成方法和应用

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