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US-20260124238-A1 - ANTIFIBROTIC AGENT, PHARMACEUTICAL COMPOSITION FOR TREATING FIBROSIS, AND METHOD FOR INACTIVATING MYOFIBROBLASTS

US20260124238A1US 20260124238 A1US20260124238 A1US 20260124238A1US-20260124238-A1

Abstract

An antifibrotic agent is provided, including a copolymer having a constitutional unit (a) containing an N-acetylglucosamine group and a constitutional unit (b) containing a structure represented by General Formula (b) (provided that a constitutional unit corresponding to the constitutional unit (a) is excluded). In General Formula (b), Yb represents a divalent linking group including an oxygen atom. Rb represents a hydrogen atom or an organic group. * represents a bonding site.

Inventors

  • Hirohiko ISE
  • Saori MATSUO

Assignees

  • KYUSHU UNIVERSITY, NATIONAL UNIVERSITY CORPORATION
  • SOMAR CORPORATION

Dates

Publication Date
20260507
Application Date
20231013
Priority Date
20221014

Claims (20)

  1. 1 . A method of inactivating myofibroblasts in a living body in need thereof, the method comprising administering to the subject a copolymer having a constitutional unit (a) containing an N-acetylglucosamine group and a constitutional unit (b) containing a structure-represented by General Formula (b), provided that a constitutional unit corresponding to the constitutional unit (a) is excluded from General Formula (b), wherein: Yb represents a divalent linking group including an oxygen atom, Rb represents a hydrogen atom or an organic group, and * represents a bonding site.
  2. 2 . The method according to claim 1 , wherein the constitutional unit (b) is a constitutional unit represented by General Formula (b-1), wherein: Rb 1 represents a hydrogen atom or an organic group, Yb 1 represents —C(═O)—O— or —C(═O)—NH—, and Rb 2 represents a hydrogen atom or an organic group.
  3. 3 . The method according to claim 1 , wherein the copolymer is a compound represented by General Formula (b-2), wherein: Lc 1 represents an (a+b)-valent linking group, Ya 2 and Yb 2 each independently represent a divalent linking group that includes an oxygen atom, GlcNAC represents an N-acetylglucosamine group, Rb 3 represents an organic group, a and b each independently represent an integer of 1 or more as long as an atomic valence is allowed, in a case where a is an integer of 2 or more, two or more Ya 2 's may be the same as or different from each other, and in a case where b is an integer of 2 or more, 2 or more Yb 2 's may be the same as or different from each other and 2 or more Rb 3 's may be the same as or different from each other.
  4. 4 . The method according to claim 1 , wherein constitutional unit (a) and constitutional unit (b) have a molar ratio of (a) to (b) that is 10:1 to 1:20.
  5. 5 . The method according to claim 2 , wherein Rb 2 in General Formula (b-1) includes at least one organic group selected from the group consisting of an ether bond, an ester bond, a urethane bond, and an amide bond.
  6. 6 . The method according to claim 1 , wherein the constitutional unit (a) is a constitutional unit containing a structure represented by Formula (a1-1-1), wherein: * represents a bonding site.
  7. 7 . The method according to claim 2 , wherein the constitutional unit (a) is a constitutional unit represented by Formula (a-1-1),
  8. 8 . The method according to claim 1 , wherein the constitutional unit (b) is a constitutional unit derived from acrylamide or a compound represented by General Formula (b1-1), wherein: k represents an integer of 1 to 12.
  9. 9 . The method according to claim 1 , wherein the copolymer is a copolymer represented by any one of General Formulae (C-1) to (C-5), wherein: R represents an alkyl group having 1 to 18 carbon atoms, a and b each independently represent an integer of 1 to 30], and Rx 1 to Rx 4 each independently represent a group represented by Formula (RX-1) or (RX-2), provided that at least one of Rx 1 to Rx 4 is a group represented by Formula (RX-1), wherein: n represents an integer of 1 or more, and * represents a bonding site.
  10. 10 . The method according to claim 1 , wherein the copolymer has a weight-average molecular weight that is within a range of 2,000 to 20,000.
  11. 11 . The method according to claim 1 , wherein the copolymer has a number-average molecular weight that is within a range of 2,000 to 15,000.
  12. 12 . The method according to claim 1 , wherein the copolymer has a ratio (Mw/Mn) of weight-average molecular weight (Mw) to number-average molecular weight (Mn) that is within a range of 1.0 to 1.7.
  13. 13 . A method of treating fibrosis in a patient or a diseased animal in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a copolymer having a constitutional unit (a) containing an N-acetylglucosamine group and a constitutional unit (b) containing a structure represented by General Formula (b), provided that a constitutional unit corresponding to the constitutional unit (a) is excluded from General Formula (b) wherein: Yb represents a divalent linking group including an oxygen atom, Rb represents a hydrogen atom or an organic group, and * represents a bonding site.
  14. 14 . A method of inactivating myofibroblasts, the method comprising binding a copolymer to the myofibroblasts, wherein: the copolymer has a constitutional unit (a) containing an N-acetylglucosamine group and a constitutional unit (b) containing a structure represented by General Formula (b), provided that a constitutional unit corresponding to the constitutional unit (a) is excluded from General Formula (b), wherein: Yb represents a divalent linking group including an oxygen atom, Rb represents a hydrogen atom or an organic group, and * represents a bonding site.
  15. 15 . The method according to claim 2 , wherein Rb 1 represents a hydrocarbon group which may have a substituent, wherein the hydrocarbon group has 1 to 12 carbon atoms.
  16. 16 . The method according to claim 2 , wherein Rb 2 represents a hydrocarbon group which may have a substituent, wherein the hydrocarbon group has 1 to 20 carbon atoms.
  17. 17 . The method according to claim 3 , wherein Rb 3 represents a hydrocarbon group which may have a substituent, wherein the hydrocarbon group has 1 to 20 carbon atoms.
  18. 18 . The method according to claim 9 , wherein the copolymer is a copolymer represented by General Formulae (C1-1),
  19. 19 . The method according to claim 9 , wherein the copolymer is a copolymer represented by General Formulae (C1-3),
  20. 20 . The method according to claim 9 , wherein the copolymer is a copolymer represented by General Formulae (C1-8), wherein: Rx 1 to Rx 3 each represent a group represented by Formula (RX-1), Rx 4 represents a group represented by Formula (RX-2), wherein: n represents an integer of 1 or more.

Description

This application is a 35 U.S.C. § 371 filing of International Patent Application No. PCT/JP2023/037231, filed Oct. 13, 2023, which claims priority to Japanese Patent Application No. 2022-165423, filed Oct. 14, 2022, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The present invention relates to an antifibrotic agent, a pharmaceutical composition for treating fibrosis, and a method for inactivating myofibroblasts. BACKGROUND ART Fibrogenesis of tissue is caused by chronic inflammation associated with repeated damage. Chronic inflammation alters fibroblasts and astrocytes, maintains tissue with myofibroblasts, and activates astrocytes. This activation promotes the enhancement of these cells and the abundant production of the extracellular matrix such as collagen. Chronic inflammatory diseases such as tissue fibrogenesis, cancer, and autoimmunity caused in this manner are caused by continuous inflammation due to intermittent and repetitive tissue damage. Severe tissue damage caused by repeated tissue damage results in the generation of a large number of cell fragments being released from dying cells. Some intracellular molecules contained in cell debris released from damaged or dead cells play a role in inflammatory cells recognizing tissue damage, and are called damage-associated molecular patterns (DAMPs) (Non-Patent Document 1). DAMPs induce an inflammatory response as a danger signal to protect host tissues from harmful situations such as tissue damage and infection. High-mobility group box 1 (HMGB1), a heat shock protein (HSP), adenosine triphosphate (ATP), and the like have clearly defined functions in cells, but these molecules act as DAMPs in the extracellular space after leaking out from dying cells. The presence of abundant DAMPs after severe tissue damage induces the recruitment and activation of immune cells that secrete inflammatory cytokines and profibrogenic cytokines (Non-Patent Document 2). These cytokines then induce differentiation of astrocytes and fibroblasts into the activated astrocytes and myofibroblasts, and promote hyperplasia or fibrogenesis during tissue remodeling (Non-Patent Document 3). As described above, tissue fibrogenesis is caused by chronic inflammation associated with repeated damage. In chronic inflammation, the excretion of parenchymal cells along with the abundant deposition of collagen finally causes dysfunction of the fibrous tissue. To recover from tissue fibrogenesis, it is necessary to selectively target myofibroblasts or activated astrocytes and suppress the activation of each cell. For example, to inhibit the expression level of collagen 1A1 and/or α-smooth muscle actin (αSMA) in human lung fibroblasts exposed to SERPINE2, a method of administering an antagonist of SERPINE2 to human lung fibroblasts has been proposed (Patent Document 1). In addition, as a therapeutic drug targeting chronic inflammation or a fibrotic site, for example, a therapeutic drug for fibrosis (Patent Document 2) has been proposed, which contains a polypeptide consisting of a specific amino acid sequence or an amino acid sequence having 85% or more identity to the specific amino acid sequence, and at least one selected from the group consisting of COL1A1, COL1A2, and αSMA. CITATION LIST Patent Documents Patent Document 1: Published Japanese Translation No. 2012-509941 of the PCT International PublicationPatent Document 2: Japanese Unexamined Patent Application, First Publication No. 2022-66026 Non-Patent Documents Non-Patent Document 1: Bianchi ME., “DAMPs, PAMPs and alarmins: all we need to know about danger.”, J. Leukoc. Biol., Vol. 81, Issue 1, pp. 1-5, 2007. doi: 10.1189/jlb.0306164. Epub 2006 Oct. 10. PMID: 17032697.Non-Patent Document 2: Bolourani, S., “The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis.”, J. Mol. Med. (Berl), Vol. 99, Issue 10, pp. 1373-1384, 2021.Non-Patent Document 3: An, P. et al., “Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis.”, Nat. Commun., Vol. 11, Article No. 2362, 2020. SUMMARY OF INVENTION Technical Problem Although there are the findings described above, there is a demand for a more effective antifibrotic agent which can induce the inactivation of myofibroblasts and can suppress fibrogenesis. Therefore, an object of the present invention is to provide an antifibrotic agent capable of inducing the inactivation of myofibroblasts, a pharmaceutical composition for treating fibrosis, containing the antifibrotic agent, and a method of inactivating the myofibroblasts. Solution to Problem As a result of intensive studies, the present inventors have found that a copolymer having a specific constitutional unit containing N-acetylglucosamine and the other constitutional units targets myofibroblasts and suppresses the activation thereof, thereby completing the present invention. The present invention includes the followi