WO2012139519A1 - Peptide cyclique et son application médicale - Google Patents

Peptide cyclique et son application médicale Download PDF

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Publication number
WO2012139519A1
WO2012139519A1 PCT/CN2012/073988 CN2012073988W WO2012139519A1 WO 2012139519 A1 WO2012139519 A1 WO 2012139519A1 CN 2012073988 W CN2012073988 W CN 2012073988W WO 2012139519 A1 WO2012139519 A1 WO 2012139519A1
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WO
WIPO (PCT)
Prior art keywords
formula
pharmaceutically acceptable
cyclic peptide
acceptable salt
phe
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2012/073988
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English (en)
Chinese (zh)
Inventor
刘克良
贾启燕
姜喜凤
刘叔文
李琳
程卯生
蔡利锋
郑保华
王昆
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Pharmacology and Toxicology of AMMS
Original Assignee
Institute of Pharmacology and Toxicology of AMMS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Institute of Pharmacology and Toxicology of AMMS filed Critical Institute of Pharmacology and Toxicology of AMMS
Publication of WO2012139519A1 publication Critical patent/WO2012139519A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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 a cyclic peptide having activity for inhibiting HIV-infected target cells, a preparation method thereof, a pharmaceutical composition containing the same, and their use in the treatment or prevention of acquired immune-deficiency syndrome (AIDS, also known as AIDS) And the use of related diseases due to HIV infection.
  • AIDS acquired immune-deficiency syndrome
  • HIV human immunodeficiency virus
  • the process of human immunodeficiency virus (HIV) infecting target cells begins with the fusion of the viral envelope and the target cell membrane, and then the viral genetic material RNA enters the target cells, replicating and releasing new viruses.
  • the entry of HIV into target cells is mediated by the viral envelope glycoprotein complex ( g pl20/ g p41) and the receptor on the target cell (the CD4 receptor and the chemokine receptor CCR-5 or CXCR-4).
  • the surface envelope of the HIV envelope glycoprotein, g pl20 binds to the CD4 receptor on the target cell and attaches to the cell; it then binds to the co-receptor of the target cell (chemokine receptor CCR5 or CXCR4, etc.);
  • the conformation of the membrane subunit g p41 is altered, and the N-terminal fusion peptide is inserted into the host cell membrane to initiate fusion of the viral envelope with the target cell membrane to complete the infection process of the virus into the host cell.
  • N Engl J Med 2003, 348:2228-33 Inhibition of any of the above steps can inhibit HIV from entering the target cells, thereby preventing and treating HIV infection.
  • HIV entry inhibitors drugs that inhibit HIV from entering target cells.
  • HIV entry inhibitors drugs that inhibit HIV from entering target cells.
  • HIV entry inhibitors drugs that inhibit HIV from entering target cells.
  • HIV fusion inhibitors drugs targeting gp41 are called HIV fusion inhibitors.
  • the object of the present invention is to find substances which have a lower molecular weight and a higher biological activity against HIV. Summary of the invention
  • the inventors have found that the cyclic peptide represented by the formula (I), or a derivative thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has a good activity of inhibiting HIV-infected target cells. Therefore, the cyclic peptide represented by the formula (I) or a derivative thereof, a stereoisomer thereof or a salt thereof which is not physiologically toxic can be used as a medicament for the treatment or prevention of HIV infection.
  • One aspect of the invention relates to a cyclic peptide of the formula I or a derivative thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • ⁇ may be a D or L natural or unnatural amino acid
  • AA 2 may be a D- or L-type natural or non-natural aromatic amino acid
  • AA 3 may be a natural or unnatural amino acid of the D or L form.
  • AAi is preferably phenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, valley Amino acid, glutamine, aspartic acid or asparagine.
  • AA 2 is preferably L or D type phenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, naphthylalanine, ⁇ -piperonyl alanine, morpholine methyl phenylalanine Acid or p-ureidophenylalanine.
  • ⁇ 3 is preferably glutamic acid, glutamine, aspartic acid, asparagine, methionine or arginine.
  • the cyclic peptide of the invention is selected from the group consisting of the following cyclic peptides or derivatives thereof or stereoisomers thereof or pharmaceutically acceptable salts thereof:
  • More preferred cyclic peptides of the invention are the polypeptides of numbers (1) and (2).
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cyclic peptide of the formula (I) or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient .
  • the present invention also relates to the use of the cyclic peptide of the formula (I) or a derivative thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a disease associated with HIV infection, such as AIDS.
  • the invention also relates to a method of treating or preventing a disease associated with HIV infection, such as AIDS, or a symptom, comprising administering to a subject in need thereof (mammal or human) a therapeutically or prophylactically effective amount of a formula (I) of the invention A step of the cyclic peptide or a derivative thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the HIV is HIV-1 type or HIV-2 type; in an embodiment of the present invention, the HIV is HIV-1 type.
  • the invention further relates to a process for the preparation of a polypeptide of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the preparation of the compound of the invention adopts solid phase synthesis method, using MBHA resin as carrier, Boc-protection strategy, HBTU as condensation reagent, DIEA as activated base, TFA as deprotection reagent, according to the amino acid sequence of the prepared compound, from C terminal to At the N-terminus, the peptide resin was synthesized according to the standard Boc solid phase peptide synthesis method.
  • cyclo means a cyclic peptide
  • derivative of the present invention includes a cysteine thiol modification in formula (I).
  • formula (I) polypeptide stereoisomer as used in the present invention means its corresponding D- or L-stereo configuration.
  • pharmaceutically acceptable salt or “non-physiologically acceptable salt” as used in the present invention means a salt or a combination thereof which retains the expected physiological activity of the parent compound without causing any unexpected toxic side effects.
  • pharmaceutically acceptable salt or “non-physiologically acceptable salt” as used in the present invention means a salt or a combination thereof which retains the expected physiological activity of the parent compound without causing any unexpected toxic side effects.
  • the salt may be: an inorganic salt such as a potassium salt, a lithium salt, a zinc salt, a copper salt, a cerium salt, a cerium salt or a calcium salt, and may also be an organic salt such as a trialkylammonium salt.
  • an inorganic salt such as a potassium salt, a lithium salt, a zinc salt, a copper salt, a cerium salt, a cerium salt or a calcium salt
  • organic salt such as a trialkylammonium salt.
  • the pharmaceutical composition of the present invention can be prepared by a conventional method in the art, for example, by mixing a polypeptide of the formula (I) with a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable carrier or excipient used in the present invention is usually a pharmaceutically acceptable carrier or excipient which is commonly used in the pharmaceutical field.
  • “commonly used pharmaceutical excipients” include any or all solvents, dispersion media, coatings, antibacterial or antifungal agents, isotonic and sustained release agents, and similar physiologically compatible preparations, suitable for intravenous injection, muscles. Injection, subcutaneous injection, or other modes of administration, such as oral administration.
  • the active compound may be coated to protect the compound from the effects of acid or other natural conditions.
  • the carrier include a saline base and various buffered aqueous solutions, ethanol or other polyols, liposomes, polylactic acid, vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and the like.
  • the polypeptide of the formula (I) of the present invention can be used alone or in the form of a pharmaceutical composition.
  • the method of administration can be oral or parenteral.
  • the preparation for oral administration may be a tablet, a capsule or a granule or the like.
  • the parenteral preparation can be an injection, a spray, a patch or the like.
  • the composition of the present invention can also be formulated into a sustained release preparation, such as a microsphere, etc.
  • AIDS Acquired Immune Deficiency Syndrome
  • AIDS Acquired Immunodeficiency Syndrome Ala
  • A Acetyl Arg (Arginine, R) Quinic Acid Boc(t-Butoxycarbonyl) Tert-Butoxy
  • HIV Human Immunodeficiency Virus
  • HIV-1 Human Immunodeficiency Virus Type I
  • the solid phase synthesis carrier used in the examples is MBHA resin, which is a product of Tianjin Nankai Synthetic Co., Ltd.; HBTU, DIEA and Boc protected natural amino acids or D-type unnatural amino acids are products of Shanghai Jill Biochemical Co., Ltd. and Chengdu Chengnuo New Technology Co., Ltd.
  • Example 1 Synthesis of Compound (1)
  • Example 3 Inhibition of HIV-1 mediated cell fusion activity assay.
  • ⁇ effector cells stably expressing HIV-1 envelope protein gpl60
  • CHO-WT cells (5xl0 5 /ml) (CHO-WT and MT-2 were obtained from NIH AIDS Research and Reference Reagent Program, USA), at 37 °C After 48 hours of culture, the formation of syncytia was observed under an inverted microscope, and the IC50 value of inhibition of cell fusion was calculated using Calcusyn software.
  • the compounds (1) and (2) correspond to the compound numbers in the examples of the present invention, and ⁇ 20 is a control drug.
  • the experimental results show that the compounds of the present invention are effective in inhibiting HIV-1 mediated cell fusion.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Genetics & Genomics (AREA)
  • AIDS & HIV (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un peptide cyclique de formule (1) présentant une action d'inhibition de l'infection à VIH. L'invention concerne également un procédé de préparation dudit peptide cyclique, une composition pharmaceutique le contenant, et son usage dans le cadre de l'inhibition de l'infection à VIH.
PCT/CN2012/073988 2011-04-13 2012-04-13 Peptide cyclique et son application médicale Ceased WO2012139519A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110091273.8 2011-04-13
CN201110091273.8A CN102731626B (zh) 2011-04-13 2011-04-13 环肽及其医药用途

Publications (1)

Publication Number Publication Date
WO2012139519A1 true WO2012139519A1 (fr) 2012-10-18

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CN (1) CN102731626B (fr)
WO (1) WO2012139519A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2025515349A (ja) * 2022-04-29 2025-05-14 セルピン ファーマ リミテッド ライアビリティ カンパニー Ｓｅｒｐｉｎペプチド誘導体およびその使用方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107236021B (zh) * 2017-06-12 2020-12-01 湖北泓肽生物科技有限公司 一种多肽衍生物的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101845079A (zh) * 2009-03-27 2010-09-29 中国人民解放军军事医学科学院毒物药物研究所 六肽或其衍生物及其医药用途
WO2011127624A1 (fr) * 2010-04-13 2011-10-20 中国人民解放军军事医学科学院毒物药物研究所 Peptide anti-vih

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101845079A (zh) * 2009-03-27 2010-09-29 中国人民解放军军事医学科学院毒物药物研究所 六肽或其衍生物及其医药用途
WO2011127624A1 (fr) * 2010-04-13 2011-10-20 中国人民解放军军事医学科学院毒物药物研究所 Peptide anti-vih

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JIA, Q.Y. ET AL.: "Short cyclic peptides derived from the C-terminal sequence of al-antitrypsin exhibit significant anti-HIV-1 activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 7, 1 April 2012 (2012-04-01), pages 2393 - 2395, XP028471731, DOI: doi:10.1016/j.bmcl.2012.02.037 *
JIANG, ZHILONG ET AL.: "Synthesis and Biological Activities of Cyclic Analogues of Thymosin al Active Fragment", CHEMICAL JOURNAL OF CHINESE UNIVERSITIES, vol. 28, no. 5, May 2007 (2007-05-01), pages 877 - 880 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2025515349A (ja) * 2022-04-29 2025-05-14 セルピン ファーマ リミテッド ライアビリティ カンパニー Ｓｅｒｐｉｎペプチド誘導体およびその使用方法

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Publication number Publication date
CN102731626B (zh) 2014-10-01
CN102731626A (zh) 2012-10-17

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