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WO2025139301A1 - Sel pharmaceutiquement acceptable de polypeptide et son utilisation - Google Patents

Sel pharmaceutiquement acceptable de polypeptide et son utilisation Download PDF

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Publication number
WO2025139301A1
WO2025139301A1 PCT/CN2024/127363 CN2024127363W WO2025139301A1 WO 2025139301 A1 WO2025139301 A1 WO 2025139301A1 CN 2024127363 W CN2024127363 W CN 2024127363W WO 2025139301 A1 WO2025139301 A1 WO 2025139301A1
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Prior art keywords
polypeptide
pharmaceutically acceptable
acceptable salt
stroke
pharmaceutical composition
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Chinese (zh)
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韩化敏
季奇
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Biocells Beijing Biotech Co Ltd
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Biocells Beijing Biotech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity

Definitions

  • Endothelin is a 21-amino acid polypeptide that can be divided into three subtypes: ET-1, ET-2, and ET-3. They have structural homology with snake venom sarafotoxin b and c (S6b, S6c). Endothelin is the most potent and longest-lasting vasoactive peptide known to date. It has strong vasoconstriction and promotes smooth muscle cell migration and proliferation. It acts on a wide range of systems in the body and is closely related to diseases such as hypertension, congestive heart failure, diabetes, cancer, and fibrosis.
  • Endothelin exerts its biological effects mainly by binding to endothelin receptors (ETR) on target cell membranes, and plays an important role in the occurrence and development of many diseases such as cardiovascular and cerebrovascular diseases, kidney diseases, diabetes, autoimmune diseases and tumors.
  • ETR endothelin receptors
  • Human ETR is divided into two subtypes, ETA and ETB, both of which are G-protein-coupled receptors (GPCR), but their functions are different.
  • GPCR G-protein-coupled receptors
  • ETBR endothelin B receptor
  • the present application provides a new pharmaceutically acceptable salt of a polypeptide and its application.
  • the polypeptides and pharmaceutically acceptable salts provided in this application are based on the mechanism research of ETBR agonists and are highly selective agonists of ETBR.
  • the polypeptides and pharmaceutically acceptable salts provided in this application extend the half-life and in vivo exposure of the drug through structure-activity relationship research and structural modification, reduce the number of administrations, and have lower side effects in animal experiments than IRL-1620, the only ETBR agonist currently in clinical research, and have a larger safety window of the drug.
  • the polypeptides and pharmaceutically acceptable salts provided in this application can be used in combination with ETBR agonists. Treatment of body-related diseases, such as rehabilitation problems in the recovery period of ischemic stroke patients, promotes better recovery of stroke patients. Specifically, this application provides the following technical solutions:
  • the present application provides a pharmaceutically acceptable salt of a polypeptide, wherein the polypeptide comprises the amino acid sequence Fum-DEEAVYFAHK(-AEEA- ⁇ E-C12)DVIW (SEQ ID NO:1) or a functional variant thereof.
  • the functional variant is a variant produced by one or more conservative substitutions in SEQ ID NO:1.
  • the conservative substitution is selected from substitutions between D and E, substitutions between V, L and I, substitutions between Y, F and W, substitutions between H, K and R.
  • the functional variant has the same or similar ETBR receptor activation activity as SEQ ID NO:1.
  • the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, ammonium salt, trifluoroacetate salt, acetate salt, hydrochloride salt, sulfate salt, and phosphate salt.
  • the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, and ammonium salt.
  • the pharmaceutically acceptable salt is a sodium salt.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of the polypeptide described in the first aspect, and a pharmaceutically acceptable carrier, excipient and/or diluent.
  • the pharmaceutical composition is a pre-lyophilized formulation.
  • the pharmaceutical composition comprises sodium chloride and/or optionally trehalose and/or cyclodextrin.
  • the pharmaceutical composition is a lyophilized preparation, preferably prepared by lyophilizing the pre-lyophilized preparation described above.
  • the pharmaceutical composition is a reconstituted formulation, preferably prepared by combining the lyophilized formulation described above with an aqueous solution.
  • the pharmaceutical composition is used to treat a disease associated with the ETBR receptor.
  • the pharmaceutical composition is used to treat, improve or prevent nervous system damage and related diseases caused by the damage, neurodegenerative diseases, anxiety, epilepsy, aortic valve stenosis or neonatal hypoxic-ischemic encephalopathy.
  • the present application provides a method for promoting the regeneration of neurovascular units in an individual, improving blood supply and oxygen supply to the nervous system, treating, improving or preventing nervous system damage in an individual and related diseases caused by the damage, neurodegenerative diseases, anxiety, epilepsy, aortic valve stenosis or neonatal hypoxic-ischemic encephalopathy, the method comprising administering to the individual a pharmaceutically acceptable salt of the polypeptide described in the first aspect or the pharmaceutical composition described in the second aspect.
  • the present application provides the use of a pharmaceutically acceptable salt of the polypeptide described in the first aspect or the pharmaceutical composition described in the second aspect in the preparation of a drug for promoting regeneration of neurovascular units, improving blood supply and oxygen supply to the nervous system, treating, improving or preventing nervous system damage in an individual and related diseases caused by the damage, neurodegenerative diseases, anxiety, epilepsy, aortic valve stenosis or neonatal hypoxic-ischemic encephalopathy.
  • the nervous system injury and related diseases caused by the injury include cerebral stroke, spinal cord injury, ischemic or traumatic injury of the brain or spinal cord, and damage to central nervous system (CNS) neurons.
  • the cerebral stroke includes ischemic stroke, hemorrhagic stroke and hemorrhagic stroke transformed from ischemic stroke; the neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease or Huntington's disease.
  • ALS amyotrophic lateral sclerosis
  • Parkinson's disease Huntington's disease.
  • the individual is a mammal, eg, a non-primate or a primate, eg, a human.
  • the present application also provides a drug comprising a pharmaceutically acceptable salt of the polypeptide described in the first aspect or the pharmaceutical composition described in the second aspect, and optionally any other active ingredients.
  • Step 1 obtaining a peptide resin of the polypeptide by solid phase peptide synthesis
  • the present invention discloses pharmaceutically acceptable salts of polypeptides and their applications. Those skilled in the art can refer to the contents of this article and appropriately improve the process parameters to achieve the same. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.
  • the present application provides a pharmaceutically acceptable salt of a polypeptide, wherein the polypeptide comprises the amino acid sequence Fum-DEEAVYFAHK(-AEEA- ⁇ E-C12)DVIW (SEQ ID NO:1) or a functional variant thereof.
  • a “functional variant” refers to a variant having the same or similar biological functions and properties as the parent.
  • a “functional variant” can be obtained by making one or more conservative substitutions in the parent.
  • the conservative substitution is selected from substitutions between D and E, substitutions between V, L and I, substitutions between Y, F and W, substitutions between H, K and R.
  • the functional variants disclosed herein also include amino acid sequences with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or even higher identity with the above-mentioned peptides.
  • identity between two proteins is determined by comparing the amino acid sequence of one protein with the sequence of the second protein substituted with its conservative amino acids. The degree of identity between two proteins is determined using computer algorithms and methods well known to those skilled in the art. The identity between two amino acid sequences is preferably determined by utilizing the BLASTP algorithm.
  • the functional variants disclosed herein include peptides having 1, 2, 3, 4, 5 or more substitutions, deletions, additions and/or insertions of amino acid residues that differ from the specific peptides disclosed above compared to the above-mentioned peptides.
  • the active peptides of the present application can be synthesized by solid phase synthesis or recombinant methods.
  • Peptidomimetics can be synthesized using a variety of protocols and methods described in the scientific literature and patent literature, such as Organic Syntheses Collective Volumes, Gilman et al. (ed.) John Wiley & Sons, Inc., NY, al-Obeidi (1998) Mol. Biotechnol. 9: 205-223; Hruby (1997) Curr. Opin. Chem. Biol. 1: 114-119; Ostergaard (1997) Mol. Divers. 3:17-27; Ostresh (1996) Methods Enzymol. 267:220-234.
  • Step 1 Weigh 0.50g (0.25mmol) of Fmoc-Trp(Boc)-Wang Resin in a reactor, add 10mL of DCM to swell for 10min, filter, wash twice with DMF, add 25% 4-methylpiperidine/DMF (volume ratio) to react for 30min to remove the Fmoc group.
  • the precipitate was added with methyl tert-butyl ether again, vortexed, centrifuged, and the supernatant was discarded.
  • the precipitate was placed in a vacuum dryer and dried for 12 hours to obtain a crude product.
  • the crude peptide was dissolved in about 1% ammonia water, filtered, and the filtrate was purified by preparative liquid phase.
  • Preparative column C18-10-100, 30 ⁇ 250mm. Flow rate: 25mL/min. Phase A: 0.1% TFA/water, phase B: 0.1% TFA/90% acetonitrile/water. Gradient elution was performed to obtain the pure target compound.
  • Step 3 Preparation of the salt (BX-229-Na) of the polypeptide (SEQ ID NO: 1)
  • the preparation column used for purification includes C18-10-100, 30 ⁇ 250 mm, and the flow rate used is 25 mL/min; the preparation liquid phase includes phase A: 0.1% TFA/water, phase B: 0.1% TFA/90% acetonitrile/water.
  • the use of a molecule or ion with an opposite charge to the drug to form a salt is expected to improve certain undesirable physicochemical properties or biopharmaceutical properties of the drug, such as changing the solubility or dissolution of the drug, reducing hygroscopicity, improving stability, changing the melting point, etc.
  • the final determination of the ideal salt form requires finding a balance between physicochemical properties and biopharmaceutical properties.
  • the selection of pharmaceutically acceptable salt forms of drugs should give priority to the following requirements: solubility, hygroscopicity, and stability to environmental factors under different states.
  • the pharmaceutically acceptable salt of the polypeptide of the present application can be any suitable pharmaceutically acceptable salt form.
  • the pharmaceutically acceptable salt of the polypeptide is a sodium salt.
  • the pharmaceutically acceptable salt of the polypeptide is a potassium salt.
  • the pharmaceutically acceptable salt of the polypeptide is an ammonium salt.
  • the pharmaceutically acceptable salt of the polypeptide is a trifluoroacetate, an acetate.
  • the pharmaceutically acceptable salt of the polypeptide is a sodium salt.
  • Acceptable salts are hydrochlorides, sulfates or phosphates.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of the polypeptide described in the first aspect, and a pharmaceutically acceptable carrier, excipient and/or diluent.
  • the filler is selected from mannitol, trehalose, dextran-40, glycine, lactose, sorbitol, cyclodextrin and sucrose, etc., wherein trehalose and cyclodextrin are preferred.
  • the lyophilized preparation of the present application comprises a pharmaceutically acceptable salt of the polypeptide described above as well as trehalose and cyclodextrin.
  • stroke includes ischemic stroke, hemorrhagic stroke, and hemorrhagic stroke converted from ischemic stroke.
  • the obtained BX-229 solid was dissolved in 0.1N potassium hydroxide aqueous solution (containing 10 equivalents of potassium hydroxide) and the salt was transferred using a preparative liquid phase.
  • Preparative column C18-10-100, 30 ⁇ 250mm. Flow rate: 25mL/min.
  • Phase A water
  • phase B acetonitrile. After loading, rinse with water for 15 minutes, and then elute the product from the preparative column by gradient elution.
  • the obtained BX-229 solid was dissolved in 5% ammonia solution (pH about 9) and the salt was transferred using a preparative liquid phase.
  • Preparative column C18-10-100, 30 ⁇ 250mm. Flow rate: 25mL/min.
  • Phase A water
  • phase B acetonitrile. After loading, rinse with water for 15 minutes, and then elute the product from the preparative column by gradient elution.
  • Example 2 EC50 determination of BX-229-Na activity on ETB receptors of different species
  • This example tests the agonist activity of BX-229-Na prepared in Example 1 on ETB receptors of different species and compares it with IRL-1620.
  • 293T-17 cells were plated in 6-well plates at a density of 650,000 per well and cultured overnight in a 37°C, 5% CO2 incubator. Then, 2.5 ⁇ g of the expression vector PCDNA3.1-hETB (human hETB sequence, CBI accession number: NM_000115.5) containing the human ETB receptor gene was transfected into each well. The cells were cultured for 48 h. After the cells expressed green fluorescence under a fluorescence microscope, they were digested with trypsin and counted. The activity of BX-229-Na on human ETB receptor was determined using the IP-One Gq kit of Cisbio Bioassays.
  • Cells were suspended with the Stim Buffer in the kit, and the cell suspension was added to a 96-well test plate. 7 ⁇ L of cell suspension (containing 30,000 cells) was added to each well.
  • the polypeptides BX-229-Na and IRL-1620 prepared in Example 1 were diluted with Stim B to 11 concentration gradients, and each concentration gradient was dissolved with Stim B to a concentration of 2 ⁇ , and 7 ⁇ L was added to the above-mentioned cells to be tested. 7 ⁇ L of PBS solution was added to the negative control wells. The plate was sealed and incubated in a cell culture incubator at 37°C for 1 hour.
  • IP1 d2 working solution 3 ⁇ L of IP1 d2 working solution and 3 ⁇ L of IP1 Tb cryptotate Antibody working solution were added to the test wells, positive control wells, and human endothelin ET1 (ET1, SEQ ID NO.: 2, CSCSSLMDKECVYFCHLDIIW (C1-C15, C3-C11)), and PBS control wells.
  • E1 human endothelin ET1
  • the average value of the 665nm signal/620nm signal value measured by the test sample at different concentrations is F.
  • the operation for determining the EC50 of canine, rat and mouse ETB receptor activity was the same as above, except that the transfection plasmids were the expression vector PCDNA3.1-DETB containing the canine ETB receptor gene (canine ETB sequence, NCBI accession number: NM_001010943.2), the expression vector PCDNA3.1-RETB containing the rat ETB receptor gene (rat ETB receptor sequence, NCBI accession number: X57764.1), and the expression vector PCDNA3.1-mETB containing the mouse ETB receptor gene (mouse ETB sequence, NCBI accession number: NM_001276296).
  • the transfection plasmids were the expression vector PCDNA3.1-DETB containing the canine ETB receptor gene (canine ETB sequence, NCBI accession number: NM_001010943.2), the expression vector PCDNA3.1-RETB containing the rat ETB receptor gene (rat ETB receptor sequence, NCBI accession number: X57764.1), and the expression vector PCDNA3.1-mET
  • This example tests the activity of BX-229-Na prepared in Example 1 on human ETA receptor.
  • 293T-17 cells were plated in 6-well plates at 650,000 per well, cultured overnight in a 37°C, 5% CO 2 incubator, and then transfected with 2.5 ⁇ g of the expression vector PCDNA3.1-hETA (hETA sequence, NCBI accession number: L06622.1) containing the human ETA receptor gene. The cells were then transfected with 2.5 ⁇ g of plasmid per well and cultured for 48 hours. After observing the cells expressing green fluorescence under a fluorescence microscope, the cells were digested with trypsin and counted. The activity of BX-229-Na on human ETA receptor was determined using the IP-One Gq kit of Cisbio Bioassays.
  • the cells were suspended with the Stim Buffer in the kit, and the cell suspension was added to a 96-well assay plate. 7 ⁇ L of the cell suspension (containing 30,000 cells) was added to each well. The polypeptide prepared in Example 1 was added to the plate. BX-229-Na and positive control peptide human endothelin ET1 (SEQ ID NO.: 2) were dissolved in Stim B to a concentration of 2 ⁇ , and 7 ⁇ L was added to the above-mentioned cells to be tested. 7 ⁇ L of PBS solution was added to the negative control wells and incubated in a cell culture incubator at 37°C for 1 hour.
  • IP1 d2 working solution 3 ⁇ L of IP1 d2 working solution and 3 ⁇ L of IP1 Tb cryptotate Antibody working solution were added to the test wells, positive control wells, and PBS control wells.
  • the plates were sealed and protected from light at room temperature (25°C ⁇ 5°C) for 1 hour.
  • the plate seal was removed and the absorbance was measured on an ID5 microplate reader as 665nm and 620nm values.
  • the ratio of the acceptor and donor emission signals in each well was calculated, i.e. (665nm signal/620nm signal) ⁇ 10 4 values.
  • the average value of the 665nm signal/620nm signal value measured by the test sample at a specific concentration is F3
  • the average value of the 665nm signal/620nm signal value measured by the positive control human endothelin ET1 at the same concentration is F5
  • the average value of the 665nm signal/620nm signal value measured by the PBS negative control is T3.
  • the activity percentage of the tested polypeptide sample relative to the positive control sample ET1 (F3-T3) ⁇ 100/(F5-T3), the results are shown in Table 2, indicating that BX-229-Na is a selective agonist of the ETB receptor.
  • This example tests the half-life of the polypeptide BX-229 prepared in Example 1 and compares it with the control IRL-1620.
  • Plasma sample administration and treatment method BX-229 and control IRL-1620 were injected into 3 C57 BL/6 mice, 60 ⁇ g/mL, and 200 ⁇ L was injected into each mouse. Blood was collected 1min, 5min, 15min, and 30min after drug injection. Protease inhibitors were added immediately after blood collection, and centrifuged at 3200rpm and 4 degrees for 10min. After taking plasma, 2 volumes of acetonitrile were added to precipitate protein, and then centrifuged at 10000rpm for 5min. After filtering with a 0.22 ⁇ m filter, the plasma concentration was calculated based on the integrated area of the control drug and the test drug, and the average value of the three test values at each time point of different drugs was calculated. At the same time, blank mouse plasma protein precipitation samples were prepared as controls, and the results are shown in Table 3.
  • Mobile phase B 0.05% TFA-10% ultrapure water-90% acetonitrile
  • Example 9 Efficacy of BX-229 sodium salt administered subcutaneously three times a week on the mouse tMCAO model
  • This example tests the efficacy of the BX-229 sodium salt (BX-229-Na) prepared in Example 1 on the mouse tMCAO model.
  • the embolus was removed 45 minutes after modeling. After suturing the incision, 1 mL of 37°C warm saline was injected subcutaneously, and the mice were placed on a heating pad until they recovered. To relieve pain, the mice were injected subcutaneously with analgesia after waking up from anesthesia. The modeling day was defined as D1, the next day as D2, and so on.
  • mice The successfully modeled C57 tMCAO mice were randomly divided into 3 groups: normal saline group, 30 ⁇ g/Kg BX-229-Na administration group, and 100 ⁇ g/Kg BX-229-Na administration group. Each group was subcutaneously administered once in the neck 4.5h after embolization (D1), and was administered once at the same time point and site on D3 and D6. The grouping and administration scheme of this experiment are shown in Table 8. There were 6 mice in the sham operation group. The drug was administered by subcutaneous injection in the neck at 2mL/kg. Garcia JH score was completed 7D and 14D after administration. After the scoring on 14D, the mice were euthanized, the brain tissue on the infarct side was taken, and the total protein was extracted. The changes of VEGF-A and BDNF protein markers in each experimental group were detected by ELISA.
  • the experimental results showed that from the analysis of the 7D Garcia JH-15 score results, there was a significant difference in the 7D score between the sham operation group and the saline solvent control group.
  • the score results of the BX-229-30 ⁇ g/Kg and BX-229-100 ⁇ g/Kg administration groups were better than those of the saline group, with a certain dose-dependent trend.
  • the total score of the Garcia JH-15 score of the BX-229-100 ⁇ g/Kg administration group was 1 point higher than that of the saline group. From the analysis of the 14D Garcia JH-15 score results, there was a significant difference in the 14D score between the sham operation group and the saline solvent control group.
  • Example 10 Efficacy of subcutaneous administration of BX-229 sodium salt and intravenous administration of IRL-1620 in tMCAO mouse model
  • This example tests the efficacy of subcutaneous administration of BX-229 sodium salt (BX-229-Na) prepared in Example 1 on the mouse tMCAO model, and compares it with intravenous administration of IRL-1620 (the administration method and dosage of IRL-1620 are derived from the animal equivalent method derived from clinical administration information).
  • the tMCAO mouse modeling method refers to Example 9.
  • the tMCAO mice with successful modeling were randomly divided into the model group and different treatment groups.
  • the detailed experimental groups are as follows: (1) The 2.7 ⁇ g/Kg IRL-1620 administration group was administered three times a day on D1, D3, and D6 after modeling. On D1, it was intravenously administered 2 hours after modeling, and then administered once every 2 hours. The administration time of D3 and D6 was the same as D1; (2) The 30 ⁇ g/Kg BX-229 administration group was administered for 7 consecutive days from D1 to D7.
  • the administration time on D1 was subcutaneous administration once 4.5 hours after modeling, and the administration time on D2-D7 was the same as D1; (3) Model (normal saline) group; and (4) Sham operation group (the sham operation group used the same method without ligating the blood vessels or inserting sutures).
  • the model group and the sham operation group were given the same dose of vehicle normal saline.

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Abstract

L'invention concerne un sel pharmaceutiquement acceptable d'un polypeptide et son utilisation. L'utilisation du sel pharmaceutiquement acceptable du polypeptide permet de prolonger la demi-vie du médicament grâce à une étude sur la relation structure-activité et une modification structurale, d'augmenter l'exposition in vivo, de réduire la fréquence d'administration, de diminuer les effets secondaires observés lors d'expériences sur les animaux et d'élargir la fenêtre thérapeutique du médicament. Le sel pharmaceutiquement acceptable du polypeptide peut être utilisé pour le traitement de maladies associées au récepteur de l'ETBR, telles que le traitement de rééducation de la phase aiguë et la phase de récupération d'un patient atteint d'une thrombose artérielle cérébrale, favorisant une meilleure récupération du patient atteint d'un accident vasculaire cérébral.
PCT/CN2024/127363 2023-12-27 2024-10-25 Sel pharmaceutiquement acceptable de polypeptide et son utilisation Pending WO2025139301A1 (fr)

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CN110799522A (zh) * 2017-07-05 2020-02-14 拜西欧斯（北京）生物技术有限公司 用于治疗、改善或预防脑出血的肽及其用途
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CN110684082A (zh) * 2019-10-08 2020-01-14 江苏诺泰澳赛诺生物制药股份有限公司 Gip和glp-1双激动多肽化合物及药学上可接受的盐与用途
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CN114605497A (zh) * 2021-02-10 2022-06-10 北京欣安诚科技有限公司 一种dapk1磷酸化底物的人工小分子干扰肽及其制药用途

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