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CN-122028898-A - Novel short-chain peptides and derivatives thereof

CN122028898ACN 122028898 ACN122028898 ACN 122028898ACN-122028898-A

Abstract

There is provided a compound of formula I, X-Y (I) wherein Y comprises a peptide fragment of formula IV, [ Ala ] m -[Lys ‑ V] n -Lys-V (IV) wherein m represents 0 or 1, n represents an integer 0, 1, 2, 3 or 4, and each V independently represents a sequence of 2 to 4 amino acids, wherein the amino acids are selected from one or more of Lys, pro, hyp, diHyp, thr, pThr, DOPA, tyr and Ser, and X represents at least one optional substituent selected from the group consisting of (I) lipids selected from vitamin A, vitamin E, cholesterol and fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons and/or one or more cyclic rings, the lipids being linear or branched, saturated or unsaturated with between 1 and 10 carbon-carbon double bonds and/or substituted with between 1 and 10-OH groups, or derivatives of any of these lipids, and/or (ii) non-steroidal anti-inflammatory drugs, useful as a pharmaceutical, in the treatment of burns, including as an adhesive, a film-forming material, a membrane, a therapeutic or a therapeutic agent, a skin, an inflammatory, and an inflammatory, a condition, and an inflammatory or an inflammatory condition of the oral, and an inflammatory condition, including a skin, and an inflammatory condition is provided.

Inventors

  • J. Hegerstrom
  • GU MING
  • KANG RUIJUAN
  • SONG MAOQIAN

Assignees

  • 艾缇亚(上海)制药有限公司

Dates

Publication Date
20260512
Application Date
20241023
Priority Date
20231023

Claims (20)

  1. 1. A compound of the formula I, X-Y(I) Wherein: y represents Z or Z-Lys-Z; Each time it is employed, Z independently represents a structural fragment of formula IV, [Ala] m -[Lys - V] n -Lys-V (IV)(SEQ ID No: 3) Wherein: m represents 0 or 1; n represents an integer of 0,1, 2, 3 or 4; v independently represents a sequence of 2 to 4 amino acids each time it is employed, wherein the amino acids are selected from one or more of Lys, pro, hyp, diHyp, thr, pThr, DOPA, tyr and Ser, X represents at least one optional substituent selected from the group consisting of: (i) Lipids selected from vitamin A, vitamin E, cholesterol and fatty acids comprising one or more carboxylic acid groups, 1 to 50 carbons and/or one or more cyclic rings, said lipids being linear or branched, saturated or unsaturated with between 1 and 10 carbon-carbon double bonds and/or substituted with between 1 and 10-OH groups, or derivatives of any of these lipids, and/or (Ii) A non-steroidal anti-inflammatory drug, which is a non-steroidal anti-inflammatory drug, And regioisomers, stereoisomers and pharmaceutically or cosmetically acceptable salts of said compounds, Provided that when X is absent, Y represents Z, and both m and n represent 0, V does not represent-Pro-Lys.
  2. 2. The compound of claim 1, wherein the amino acid in V is selected from the group consisting of Lys, pro, hyp, diHyp, thr, pThr, DOPA and Tyr.
  3. 3. The compound according to any one of the preceding claims, wherein the amino acid in V is selected from the group consisting of Pro, hyp, lys, tyr and DOPA.
  4. 4. A compound according to any one of the preceding claims, wherein the amino acid adjacent to Lys in V is selected from the group consisting of Pro and Hyp.
  5. 5. A compound according to any one of the preceding claims, wherein V represents a 2 amino acid sequence.
  6. 6. The compound of claim 5, wherein the C-terminal amino acid is selected from Lys, tyr, and DOPA.
  7. 7. The compound of claim 6, wherein Z comprises the sequence: Lys-Pro-Lys(SEQ ID No: 9); Lys-Pro-Tyr(SEQ ID No: 10); Lys-Pro-DOPA(SEQ ID No: 11); Lys-Hyp-Tyr(SEQ ID No: 12); Lys-Hyp-DOPA (SEQ ID No: 13), or Lys-Hyp-Lys(SEQ ID No: 14)。
  8. 8. The compound of claim 6 or claim 7, wherein Z comprises the sequence: Lys-Pro-Tyr(SEQ ID No: 10); Lys-Pro-DOPA(SEQ ID No: 11); Lys-Hyp-Tyr(SEQ ID No: 12); Lys-Hyp-DOPA (SEQ ID No: 13), or Lys-Hyp-Lys(SEQ ID No: 14)。
  9. 9. The compound of claim 6, wherein Z comprises the sequence: Lys-Hyp-Tyr(SEQ ID No: 12); Lys-Hyp-Lys (SEQ ID No: 14), or Lys-Hyp-Hyp-Lys(SEQ ID No: 18)。
  10. 10. A compound according to any one of claims 1 to 9, wherein V represents a 3 or 4 amino acid sequence.
  11. 11. The compound of claim 10, wherein the C-terminal amino acid in V is Lys.
  12. 12. The compound of claim 11, wherein at least one other amino acid in the sequence defining V is Hyp.
  13. 13. The compound according to any one of claims 10 to 12, wherein Z comprises the sequence: Lys-Pro-Pro-Lys(SEQ ID No: 15); Lys-Pro-Hyp-Lys(SEQ ID No: 16); Lys-Hyp-Pro-Lys(SEQ ID No: 17); Lys-Hyp-Hyp-Lys(SEQ ID No: 18); Lys-Pro-DOPA-Hyp-Lys(SEQ ID No: 19); Lys-Pro-DOPA-Pro-Lys(SEQ ID No: 20); Lys-Hyp-DOPA-Hyp-Lys(SEQ ID No: 21); Lys-Hyp-DOPA-Pro-Lys(SEQ ID No: 22); Lys-Pro-Tyr-Pro-Lys(SEQ ID No: 23); Lys-Hyp-Tyr-Pro-Lys(SEQ ID No: 24); Lys-Pro-Tyr-Hyp-Lys (SEQ ID No: 25), or Lys-Hyp-Tyr-Hyp-Lys(SEQ ID No: 26)。
  14. 14. A compound according to any one of the preceding claims, wherein m represents 0.
  15. 15. A compound according to any one of the preceding claims, wherein n represents 0 such that Z is defined by formula Lys-V.
  16. 16. A compound according to any one of claims 1 to 14, wherein n represents 1 such that Z is defined by the formula Lys-V-Lys-V.
  17. 17. The compound of claim 16, wherein V represents a2 amino acid sequence.
  18. 18. The compound of claim 16 or claim 17, wherein Z comprises the sequence: Lys-Hyp-Tyr-Lys-Hyp-DOPA(SEQ ID No: 27); Lys-Hyp-Tyr-Lys-Pro-Lys(SEQ ID No: 28); Lys-Hyp-Tyr-Lys-Pro-Tyr(SEQ ID No: 29); Lys-Hyp-Tyr-Lys-Pro-DOPA(SEQ ID No: 30); Lys-Hyp-DOPA-Lys-Hyp-Tyr(SEQ ID No: 31); Lys-Hyp-DOPA-Lys-Pro-Lys(SEQ ID No: 32); Lys-Hyp-DOPA-Lys-Pro-Tyr(SEQ ID No: 33); Lys-Hyp-DOPA-Lys-Pro-DOPA(SEQ ID No: 34); Lys-Pro-Lys-Lys-Hyp-Tyr(SEQ ID No: 35); Lys-Pro-Lys-Lys-Hyp-DOPA(SEQ ID No: 36); Lys-Pro-Lys-Lys-Pro-Tyr(SEQ ID No: 37); Lys-Pro-Lys-Lys-Pro-DOPA(SEQ ID No: 38); Lys-Pro-Tyr-Lys-Hyp-Tyr(SEQ ID No: 39); Lys-Pro-Tyr-Lys-Hyp-DOPA(SEQ ID No: 40); Lys-Pro-Tyr-Lys-Pro-Lys(SEQ ID No: 41); Lys-Pro-Tyr-Lys-Pro-DOPA(SEQ ID No: 42); Lys-Pro-DOPA-Lys-Hyp-Tyr(SEQ ID No: 43); Lys-Pro-DOPA-Lys-Hyp-DOPA(SEQ ID No: 44); Lys-Pro-DOPA-Lys-Pro-Lys(SEQ ID No: 45); Lys-Pro-DOPA-Lys-Pro-Tyr(SEQ ID No: 46); Lys-Hyp-Tyr-Lys-Hyp-Tyr(SEQ ID No: 47); Lys-Hyp-DOPA-Lys-Hyp-DOPA(SEQ ID No: 48); Lys-Pro-Lys-Lys-Pro-Lys(SEQ ID No: 49); Lys-Pro-Tyr-Lys-Pro-Tyr(SEQ ID No: 50); Lys-Pro-DOPA-Lys-Pro-DOPA(SEQ ID No: 51); Lys-Hyp-Lys-Lys-Hyp-Tyr(SEQ ID No: 52); Lys-Hyp-Lys-Lys-Hyp-DOPA(SEQ ID No: 53); Lys-Hyp-Lys-Lys-Pro-Lys(SEQ ID No: 54); Lys-Hyp-Lys-Lys-Pro-Tyr(SEQ ID No: 55); Lys-Hyp-Lys-Lys-Pro-DOPA(SEQ ID No: 56); Lys-Hyp-Tyr-Lys-Hyp-Lys(SEQ ID No: 57); Lys-Hyp-DOPA-Lys-Hyp-Lys(SEQ ID No: 58); Lys-Pro-Lys-Lys-Hyp-Lys(SEQ ID No: 59); Lys-Pro-Tyr-Lys-Hyp-Lys(SEQ ID No: 60); Lys-Pro-DOPA-Lys-Hyp-Lys (SEQ ID No: 61), or Lys-Hyp-Lys-Lys-Hyp-Lys(SEQ ID No: 62)。
  19. 19. A compound according to any one of the preceding claims wherein Y represents Z.
  20. 20. A compound according to any one of claims 1 to 18, wherein Y represents Z-Lys-Z.

Description

Novel short-chain peptides and derivatives thereof Technical Field The present invention relates to novel peptides, the use of such peptides as pharmaceutically active ingredients or in other ways in human medicine, and pharmaceutical compositions comprising said peptides. In particular, the invention relates to the use of these peptides and compositions in the treatment of a variety of conditions including inflammation. Background Inflammation is typically characterized by a local tissue response to invasion by, for example, microorganisms, certain antigens, damaged cells, or physical and/or chemical factors. The inflammatory response is generally a protective mechanism for destroying, diluting or sequestering harmful agents and damaged tissue, as well as for initiating tissue healing. Inflammation may be caused by physical trauma, infection, some chronic diseases (e.g., psoriasis and autoimmune diseases, such as rheumatoid arthritis), and/or chemical and/or physiological reactions to external stimuli (e.g., as part of an allergic reaction). A complex series of events may be involved in which inflammatory mediators increase blood flow and distension of local blood vessels, leading to redness and heat and exudation of body fluids, often leading to local swelling, migration of leukocytes into inflamed areas, and pain. Many conditions/disorders are characterized by and/or caused by abnormal, tissue damaging inflammation. Such conditions are typically characterized by activation of immune defense mechanisms, resulting in greater than beneficial effects on the host, and are often associated with varying degrees of tissue redness or hyperemia, swelling, hyperthermia, pain, itching, cell death, tissue destruction, cell proliferation and/or loss of function. Examples include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, psoriasis, glomerulonephritis and transplant rejection. Typically, a complex series of events lead to inflammatory changes, such as increased blood flow through local vasodilation, resulting in redness and heat, extravasation of leukocytes and plasma, often resulting in local swelling, activation of sensory nerves (leading to some tissue pain), and loss of function. These inflammatory changes are triggered by a series of cellular and biochemical events involving cells like neutrophils, monocytes, macrophages and lymphocytes, as well as inflammatory mediators such as vasoactive amines, cytokines, complement factors and reactive oxygen species. In addition, inflammation plays a key role in the wound healing process. Thus, wounds and burns can be categorized as conditions associated with inflammation. The conventional wisdom in the art is that anti-inflammatory drugs should not be applied directly to open wounds, as this would be detrimental to the progress of wound healing. Fibrosis is defined by excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM), such as collagen and fibronectin) in and around inflamed or damaged tissue. Although collagen deposition is typically a reversible part of wound healing, collagen deposition may often evolve into a progressively irreversible fibrotic response if tissue damage is severe, or if the wound healing response itself becomes deregulated. Furthermore, fibrosis is known to be a major cause of morbidity and mortality in many chronic inflammatory diseases as well as end-stage liver disease, kidney disease, idiopathic Pulmonary Fibrosis (IPF) and heart failure. It is also a pathological feature of many chronic autoimmune diseases such as scleroderma, rheumatoid arthritis, crohn's disease, ulcerative colitis, myelofibrosis and systemic lupus erythematosus. Fibrosis may also affect the pathogenesis of many progressive muscle diseases, metastasis and graft rejection. An important part of mefp-1 consists of 70 to 90 tandem decapeptidic repeats of Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID No: 1; see Waite, int. J. Addition AND ADHESIVES, 1987, 7, 9-14). This decapeptide sequence may be isolated as a low molecular weight derivative of naturally occurring MAP, or may be synthesized, for example, as described by Yamamoto in j. See also Dalsin et al, j. Am. chem. Soc., 2003, 125, 4253-4258. Also disclosed are analogs of the decapeptides, particularly Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID No: 2). See, for example, US 5,616,311 and WO 96/39128, and international patent applications WO 2019/007455 A1, WO 2019/228307 A1, WO 2021/047648 A1, WO 2011/110061 A1 and WO 2021/110064 A1. Japanese patent application JP 2003238589A discloses certain di-and tripeptides as angiotensin converting enzyme inhibitors. The use of lipid-peptide conjugates (such as palmitoyl tetrapeptide-7, palmitoyl tripeptide-1 and other palmitoyl oligopeptides) in anti-aging cosmetics has been disclosed, for example, in MS ferrora, cosmetics, 2000, 7, 91. See also Kamysz et al, which discloses palmitoyl tripeptides as antimicrob