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WO2014194835A1 - Dimère chimique peptidique mimétique d'érythropoïétine et application correspondante - Google Patents

Dimère chimique peptidique mimétique d'érythropoïétine et application correspondante Download PDF

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Publication number
WO2014194835A1
WO2014194835A1 PCT/CN2014/079221 CN2014079221W WO2014194835A1 WO 2014194835 A1 WO2014194835 A1 WO 2014194835A1 CN 2014079221 W CN2014079221 W CN 2014079221W WO 2014194835 A1 WO2014194835 A1 WO 2014194835A1
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WIPO (PCT)
Prior art keywords
anemia
epo
erythropoietin
pharmaceutically acceptable
red blood
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Ceased
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PCT/CN2014/079221
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English (en)
Chinese (zh)
Inventor
刘克良
梁远军
许笑宇
颜玲娣
董华进
宫泽辉
冯思良
郄建坤
贾启燕
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/505—Erythropoietin [EPO]
    • 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
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to an erythropoietin mimetic peptide chemical dimer, a process for preparing the same, a pharmaceutical composition containing the same, and the erythropoietin mimetic peptide chemical dimer in prevention or
  • Erythropoietin is a hematopoietic growth factor (HGF) that is required for erythropoiesis. It contains 165 amino acids and has a molecular weight of about 30.4 kD. 40% of the molecular weight is the result of glycosylation modification, and the side chain hydroxyl group is 0-glycosylated. In humans, EPO is mainly produced in the kidneys of the kidneys and fetuses and is synthesized and released by the perivascular capillary endothelial cells of the renal tubules.
  • HGF hematopoietic growth factor
  • EPO acts as a cytokine in bone marrow hematopoietic tissue to promote erythropoiesis, thereby increasing the concentration of hemoglobin to ensure adequate oxygen transport from the lungs to aerobic tissue.
  • the production of EPO is inversely related to the oxygen concentration in the tissue.
  • tissue is hypoxic, the production of EPO is increased to ensure that all tissues and organs receive sufficient oxygen supply.
  • the plasma EPO concentration is in the range of 10-25 mU/mL, the normal level of hemoglobin (12-17 g/dL) can be maintained with a half-life of about 5 h.
  • EPO In addition to promoting red blood cell production in hematopoietic tissue, EPO also plays an important role in non-hematopoietic tissues and organs, such as promoting the growth and development of some tissues and organs, participating in cardiovascular formation, repair and repair of myocardial membrane damage, and EPO is also involved in brain-pairing. The response process of neuronal damage and the process of wound healing.
  • hematopoietic progenitor cells are first produced from bone marrow, and granulocytes (Gerulocyte, G)-Erythroid (E)-monocyte (Monocyte, M)-megakaryocytes are formed by various cytokines.
  • the colony forming units of ( Megakaryocyte , M ) are further differentiated into erythroid colony forming units (CFUe) by Erythroid burst-forming units (BFUe).
  • EPO EPO
  • EPO receptor which binds to the surface of CFUe, forms young red blood cells, which further differentiate into reticulocytes and finally form red blood cells.
  • EPO is the most important regulator of erythropoiesis. Therefore, lack of EPO is likely to cause anemia.
  • a variety of secondary anemias are caused by insufficient production of cytokine EPO.
  • Studies have shown that EPO can be used to treat anemia caused by multiple causes (Dai Xiaoying, Chen Xiaonong, Research progress in the treatment of anemia caused by recombinant human erythropoietin, Zhejiang Clinical Medicine, Vol. 6, No. 9, September 827-828).
  • ESAs drugs mainly EPO receptors
  • EPO drugs have been a hot spot in drug research, sales of EPO products continue to be the fourth highest-selling drug, and the EPO market continues to grow.
  • ESAs drugs have dominated the market for treatment of secondary anemia.
  • phage display technology was used to scan EPO receptors with a combinatorial library consisting of random peptide sequences, and many short peptides with no sequence correlation with endogenous EPO were obtained. These short peptides can bind to EPO receptors and trigger A series of signal transductions promote the proliferation of cell lines and have the same mechanism of action as EPO.
  • the half effective concentration (EC 50 ) of these short peptides is at least 200 nM, which is much higher than the EC 5 of EPO measured at the same time. (20pM), in addition, their in vivo stability is also poor, and therefore, the drug-making conditions cannot be satisfied.
  • the discovery of these peptide sequences has served as a guide for subsequent research.
  • the EPO receptor is activated by the dimerization of the EPO receptor by the ligand i, in 1999, Oded Livnah confirmed from the crystal structure that the dimerization conformation of the ligand (the erythropoietin peptide herein) is also The key to stimulating the biological effects of EPO receptors (Science 1999, 283: 987-990). Therefore, in order to further increase the activity of the sequence (la), the present invention obtains a chemical dimer based on the sequence (la) by chemical means on the ⁇ 3 ⁇ 4 of the Chinese patent 201210170307.7, thereby providing a red blood cell with higher biological activity.
  • the peptone mimetic peptide and its pharmaceutically acceptable salt is also used.
  • the present inventors have surprisingly found that the erythropoietin peptidomimetic peptide obtained by chemical dimerization of the single-chain erythropoiesis mimetic peptide has a more active EPO receptor agonistic activity.
  • the present invention has been completed based on the above findings. Summary of invention
  • the first aspect of the present invention provides an erythropoietin mimetic peptide chemical dimer having the following formula (I), or a pharmaceutically acceptable salt thereof
  • a second aspect of the invention provides a process for the preparation of the erythropoietin mimetic peptide dimer of the first aspect of the invention, or a pharmaceutically acceptable salt thereof.
  • a third aspect of the invention provides the use of the erythropoietin mimetic peptide dimer of any one of the first aspects of the invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the erythropoietin mimetic peptide dimer of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • a fifth aspect of the invention provides a method of activating an EPO receptor in a subject in need thereof and a method of treating a disease or condition associated with low activity of EPO and its receptor.
  • a sixth aspect of the present invention provides the erythropoietin mimetic peptide dimer of the first aspect of the present invention, which is a preventive and/or therapeutic agent for an EPO receptor agonist or a disease or symptom associated with low activity of EPO and its receptor, Or a pharmaceutically acceptable salt thereof.
  • a seventh aspect of the invention provides a composition for activating an EPO receptor in a subject in need thereof, or for preventing and/or treating a combination of diseases and/or symptoms associated with low activity of EPO and its receptor And the erythropoietin mimetic peptide dimer of the first aspect of the invention, or a pharmaceutically acceptable salt thereof.
  • the first aspect of the present invention provides an erythropoietin mimetic peptide represented by the following formula (I), or a pharmaceutically acceptable salt thereof,
  • P is a erythropoiesis-producing peptide
  • n, m is any integer between 1 and 5 (for example, 1, 2, 3, 4, 5);
  • R is H, or R is a natural amino acid of ⁇ -alanine, ⁇ -aminobutyric acid, or L-form or D-form or a derivative thereof, and its carboxyl group forms an amide structure with hydrazine.
  • the connecting arm means where R, n, m are defined by the same formula (I).
  • the natural amino acid includes alanine (Ala), valine (Val), leucine (Leu), isoleucine (lie), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Th), cysteine (Cys), tyrosine (Tyr), aspartame Amide (Asn), glutamine (Gin), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu).
  • the erythropoietin peptidomimetic chemical dimer is prepared according to the following steps: (1) using Rink-amide resin as a solid phase carrier, and HBTU-HOBt As a condensing agent, according to the amino acid sequence of the erythropoietin mimetic peptide to be obtained, the corresponding amino acid protected by Fmoc is used as a raw material, and the peptide resin is synthesized according to a standard Fmoc solid phase polypeptide synthesis method; (2) then trifluoroacetic acid: benzene Methyl sulfide: m-cresol: ethanedithiol: a mixture of water (for example, the volume ratio of these five is 8.25:0.5:0.5:0.25:0.5) as a lysate, at 0-40.
  • the peptide is deprotected by C and cleaved from the resin (for example, at about 0 C for about 30 minutes, then at room temperature for 90 minutes); (3) Dissociation of cysteine in the resulting linear peptide molecule
  • the thiol is oxidized to form a cyclic peptide; (4) an optional purification step to obtain a single-stranded erythropoiesis mimetic peptide la; (5) using a suitable tether, reacting with two peptide chains to form a dimer, optionally obtaining a purification step Dimer.
  • the third aspect of the invention provides the use of the erythropoietin mimetic peptide chemical dimer of any one of the first aspects of the invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament as an EPO receptor agonist.
  • the present invention also provides the erythropoietin mimetic peptide chemical dimer of any one of the first aspects of the present invention, or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment for lack of erythropoietin or red blood cell deficiency or Use in a drug characterized by a defect, or a drug associated with a disease and/or symptom associated with an EPO or EPO receptor activity.
  • the disease characterized by lack of erythropoietin or red blood cell deficiency or deficiency, or diseases and/or symptoms associated with low activity of EPO or EPO receptors means anemia caused by various causes.
  • the various causes of anemia include, but are not limited to, red blood cell defects, low red blood cell count, low hemoglobin content, myelodysplastic syndrome, human immunodeficiency virus infection, autologous blood collection, bone marrow transplantation, Anemia caused by hemoglobinopathy, renal anemia, tumor or cancer-related anemia, anemia in premature infants, anemia after surgery, maternal anemia, aplastic anemia, or other anemia.
  • the anemia caused by the hemoglobinopathy is, for example, thalassemia, sickle cell anemia.
  • the renal anemia mainly refers to anemia caused by chronic renal failure.
  • the tumor or cancer-related anemia can be caused by various factors, and mainly includes tumor factors (such as blood loss, hemolysis, bone marrow involvement) or factors for tumor treatment (such as bone marrow of chemotherapy). Inhibition, tumor radiation therapy, etc.) two aspects.
  • the other anemia is, for example, anemia caused by chronic inflammation or infection.
  • a fourth aspect of the invention provides a pharmaceutical composition comprising the erythropoietin peptidomimetic chemical dimer of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • a fifth aspect of the invention provides a method of activating an EPO receptor in a subject in need thereof, and a method of treating a disease or condition associated with low activity of EPO and its receptor, the method comprising preventing or treating a subject in need thereof A therapeutically effective amount of the erythropoietin mimetic peptide chemical dimer, or a pharmaceutically acceptable salt thereof, of the first aspect of the invention.
  • a sixth aspect of the present invention provides the erythropoietin mimetic peptide chemical dimer of the first aspect of the present invention, which is a preventive and/or therapeutic agent for an EPO receptor agonist or a disease or symptom associated with EPO and its receptor activity Or a pharmaceutically acceptable salt thereof.
  • a seventh aspect of the invention provides a composition for activating an EPO receptor in a subject in need thereof, or for preventing and/or treating a combination of diseases and/or symptoms associated with low activity of EPO and its receptor And the erythropoietin mimetic peptide chemical dimer of the first aspect of the invention, or a pharmaceutically acceptable salt thereof.
  • the disease and/or condition associated with low activity of the EPO or EPO receptor is renal anemia.
  • any aspect of the invention or any one of the aspects of the invention is equally applicable to any of the other aspects or any of the other aspects, as long as they do not contradict each other, of course, when applied to each other If necessary, the corresponding features can be appropriately modified.
  • the "any” refers to any of the sub-aspects of the first aspect of the invention; when otherwise mentioned in a similar manner, It also has the same meaning.
  • the term "effective amount” refers to a dose that can achieve treatment, prevention, alleviation, and/or alleviation of a disease or condition described herein in a subject.
  • the term "pharmaceutical composition” refers to a substance that can be used to effect treatment, prevention, alleviation and/or alleviation of the diseases, conditions, symptoms of the invention in a subject.
  • the term "subject,” or “patient,” may refer to an animal that receives the compositions and extracts of the invention to treat, prevent, ameliorate, and/or alleviate the diseases, disorders, symptoms of the invention. , especially mammals, such as humans, dogs, monkeys, cows, horses, etc.
  • disease or condition refers to a physical condition of the subject that is associated with the disease or condition described herein.
  • % is generally a percentage by weight/weight for the total material solids and generally a weight/volume percentage for the total material liquid.
  • percentage is generally a percentage of volume/volume.
  • erythropoietin mimetic peptide refers to a sequence of
  • erythropoietin mimetic peptide chemical dimer refers to a dimer formed by chemically linked "erythropoietin mimetic peptide”.
  • the acid of the present invention is an L-type acid, and the D-type acid is specifically indicated.
  • a disease characterized by a deficiency or deficiency in erythropoietin or red blood cells, or a disease and/or symptom associated with an EPO or EPO receptor means achieving prevention and prevention by agonizing EPO receptors.
  • diseases for treatment purposes mainly refers to various causes Anemia caused by diseases such as red blood cell defects, low red blood cell count, low hemoglobin content, tumor release, and chemotherapy leading to anemia.
  • a chemical (di)-based chemical dimer is obtained by chemical means, which provides a more biologically active erythropoietin mimetic peptide and its usable salt and a preparation method thereof.
  • the present inventors have found that by the formation of a chemical dimer, a higher EPO receptor agonistic activity is obtained, which provides a possibility of obtaining good pharmaceutical activity.
  • One of the objects of the present invention is to provide an erythropoietin mimetic peptide chemical dimer having a structure in which a dimer is formed by a chemical tether in addition to a erythropoiesis-producing peptidomimetic.
  • the erythropoietin mimetic peptide chemical dimer of the present invention is described in detail in the structure of formula (I) and its definitions described herein.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the above erythropoietin peptidomimetic chemical dimers, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to the use of a compound of the invention in the manufacture of a medicament for the treatment and prevention of anemia.
  • the anemia is, for example, anemia caused by renal anemia, tumor release, and chemotherapy.
  • the invention further relates to the use of a compound of the invention for the treatment and prevention of anemia and associated red blood cell defects or symptoms.
  • erythropoietin mimetic peptide chemical dimer having the structure of formula (I):
  • P is a erythropoiesis-producing peptide
  • n, m is any integer between 1 and 5;
  • R is H, or R is a natural amino acid of ⁇ -alanine, ⁇ -aminobutyric acid or L-form or D-form or a derivative thereof, and its carboxyl group forms an amide structure with hydrazine.
  • An erythropoietin mimetic peptide chemical dimer according to any one of the invention, which is selected from the group consisting of:
  • the amino acids are all L-type amino acids.
  • the preparation of the compound of the present invention adopts a conventional polypeptide synthesis method, including a solid phase polypeptide synthesis method, a liquid phase polypeptide synthesis method, and a solid phase-liquid phase polypeptide synthesis method, and the amino acid adopts a Fmoc-/tBu- or Boc-/Bzl-protection strategy.
  • connection method adopts a method of sequentially connecting from the N-terminus to the C-terminus, or synthesizing the fragment first, and then connecting the fragments, and solid-phase synthesis uses various resins capable of forming an amide end as a carrier (such as MBHA, PAL, Rink amide resin, etc.)
  • the condensation reaction (such as DCC/HOBT, BOP/DIE A, HBTU/HOBt, TBTU, etc.) is carried out by various common condensing agents, and after the reaction, the peptide is cleaved from the resin with trifluoroacetic acid or without HF.
  • the crude peptide forms a cyclic peptide by oxidizing two thiol groups in the molecule, and is isolated and purified to obtain a single-chain peptide, which is then chemically reacted with a suitable tether to form a dimer product, and the final product is determined by MALDI-TOF-MS.
  • the compounds of the invention have an agonistic effect on EPO receptors at the cellular level.
  • the compounds of the present invention have an effect of increasing the number of red blood cells and the hemoglobin content in normal mice.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient an effective amount of at least one erythropoietin mimetic peptide chemical dimer or a non-physiologically toxic salt thereof, together with a conventional pharmaceutical excipient or adjuvant.
  • conventional pharmaceutical excipients or adjuvants include any or all solvents, dispersion shields, coatings, antibacterial or antifungal agents, isotonic and sustained release agents, and similar physiologically compatible preparations, suitable for intravenous Injection, intramuscular, subcutaneous, or other non-digestive administration is preferred.
  • the active compound may be coated to protect the compound from the action of acid or other natural conditions.
  • pharmaceutically acceptable salt means that the expected physiological activity of the parent compound can be retained without any expectation. Salts with side effects, or compositions containing them, for example: hydrochloride, hydrobromide, sulfate, phosphate, nitrate, and acetate, oxalate, tartrate, succinate, apple Acid salts, benzoates, pamoate, alginate, sulfonate, naphthalene sulfonate, and the like.
  • the erythropoietin peptidomimetic chemical dimer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same may be administered in any manner known in the present invention, such as oral, intramuscular, subcutaneous, nasal administration, etc., administration agent Types such as tablets, capsules, buccal tablets, chewable tablets, tinctures, suspensions, transdermal agents, microencapsulated agents, implants, syrups and the like. It may be a general preparation, a sustained release preparation, a controlled release preparation, and various microparticle delivery systems. In order to formulate a unit dosage form into tablets, various biodegradable or biocompatible carriers well known in the art can be used.
  • the carrier examples include, for example, a saline base and various buffered aqueous solutions, ethanol or other polyols, liposomes, polylactic acid, vinyl acetate, polyhepatic, polyglycolic acid, collagen, polyorthoesters and the like.
  • the dose of the erythropoietin mimetic peptide chemical dimer or a pharmaceutically acceptable salt thereof in the present invention depends on many factors such as the sexual shield and severity of the disease to be prevented or treated, the sex, age, and weight of the patient or animal. , sensitivity and individual response, the particular compound used, the route of administration, the number of doses, and the desired therapeutic effect.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms.
  • Ala represents alanine
  • Gly means glycine
  • Leu leucine
  • Lys stands for lysine
  • Fmoc means ⁇ methoxy
  • DMF dimercaptoacetamide
  • DCC represents dicyclohexylcarbodiimide
  • HOBt stands for 1-hydroxybenzotriazole
  • TFA stands for trifluoroacetic acid
  • EDT stands for mercaptoethanol
  • HBTU 2-(1 ⁇ -1-hydroxybenzotriazole)-1,1,3,3-tetradecylurea
  • the present invention provides a general and/or specific description of the materials used in the test face and the test methods. While many of the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein.
  • the solid phase synthesis carrier Rink-amide resin used in the examples is Tianjin Nankai Synthetic Co., Ltd.; HOBT, HBTU, DIEA and Fmoc-protected amino acids are provided by Shanghai Jill Biochemical Co., Ltd.
  • reaction mixture was filtered to remove insoluble matter, the organic solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate was added, in a separatory funnel successively with saturated NaHC0 3, saturated NaCl, 10% HC1 aqueous solution, washed with saturated NaCl, the organic layer was dried over anhydrous Na 2 S0 4 is dry. Filtration and concentration gave 1.14 g of a blister 2a solid, yield 71%.
  • the method for detecting EPO activity in vitro is mainly based on the study of EPO-induced proliferation and/or differentiation of EPO-sensitive cells.
  • TF-1 cells purchased from GenScrip
  • the TF-1 cell line was first isolated from human erythroblastic leukemia cells, which expresses EPOR. Proliferation of TF-1 cells is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) Or interleukin 3 (IL-3).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-3 interleukin 3
  • EPO also induces proliferation of TF-1 cells and has been widely accepted as a method for detecting EPO activity in vitro (T Kitamura, et al. Blood. 1989, 73: 375-380. S Chretien, et al.
  • erythropoietin mimetic peptide chemical dimers of the present invention both have the EPO receptor-mediated pro-cell proliferative activity, and the activity is more than 100 times higher than la.
  • Biological face example 2 Evaluation of erythrocyte activity in normal mice
  • Test methods Adult male mice were randomly divided into 5 groups, about 10 in each group. The animals were continuously administered for 7 days, once a day, subcutaneously (sc), and the blood was measured at the end of the test (trusted by 307 hospitals). RhEPO (recombinant EPO, Cyclone, 5000 IU/mL, Sihuan Biopharmaceutical Co., Ltd.) was used as a positive control.
  • the vehicle is 0.1% BSA in normal saline; animals are administered continuously for 7 days, once per day, sc; */; ⁇ 0.05 ; ** /; ⁇ 0.01; *** /; ⁇ 0.001 compared with the vehicle group; # /; ⁇ 0.05 compared with the solvent group compared with the rhEPO group; preliminary results show that la is below the 5mg / kg dose There is no significant reddening effect.

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Abstract

L'invention concerne un dimère chimique peptidique mimétique d'érythropoïétine et une application correspondante et concerne en particulier un dimère chimique peptidique mimétique d'érythropoïétine représenté dans la formule (I) ou un sel médical correspondant et une composition contenant le dimère chimique peptidique mimétique d'érythropoïétine ou un sel médical correspondant. L'invention concerne également une application du dimère chimique peptidique mimétique d'érythropoïétine ou du sel médical correspondant. Les dimères chimiques peptidiques mimétique d'érythropoïétine ou le sel médical correspondant de la présente invention présente une activité d'érythropoïèse souhaitable.
PCT/CN2014/079221 2013-06-07 2014-06-05 Dimère chimique peptidique mimétique d'érythropoïétine et application correspondante Ceased WO2014194835A1 (fr)

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CN106279398B (zh) * 2015-06-26 2019-06-28 天津药物研究院有限公司 一种促红细胞生成素模拟肽及其制备方法和应用
CN105085653B (zh) * 2015-08-26 2019-01-08 天津药物研究院有限公司 一种促红细胞生成素模拟肽及其制备方法和应用
CN105148257B (zh) * 2015-09-18 2018-12-04 中国人民解放军第三军医大学 促红细胞生成素来源肽在制备治疗代谢综合征的药物中的应用
CN106554395B (zh) * 2015-09-30 2019-08-16 天津药物研究院有限公司 一种长效促红细胞生成素模拟肽及其制备方法和应用
CN106608913B (zh) * 2015-10-22 2020-05-05 天津药物研究院有限公司 一种1，2，3-丙三酸偶联的epo拟肽衍生物及其制备方法和应用
CN109336963B (zh) * 2018-11-20 2021-06-08 中国人民解放军军事科学院军事医学研究院 促红细胞生成素模拟肽二聚体及其制备方法和用途

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