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CN-122028935-A - Lipid targeting hepatic asialoglycoprotein receptor and uses thereof

CN122028935ACN 122028935 ACN122028935 ACN 122028935ACN-122028935-A

Abstract

Provided herein are compounds having structures (I), (II), (III) or (IV), wherein in these structures (I), (II), (III) and (IV), each R 1 is independently selected from an aliphatic alkyl C 4 -C 100 group, optionally substituted with one or more of alkenyl, alkynyl, hydroxy, amide, ester and/or ether groups, R 2 is selected from [ -OCH 2 CH 2 -] p or (a), and R 3 is selected from formula (V) and formula (VI): (V), (VI). M + is selected from alkali metal ions, alkaline earth metal ions, or primary, secondary or tertiary ammonium ions, and M, p and s are independently selected from integers from 1 to 120. The compounds are useful as therapeutic agents targeting hepatic asialoglycoprotein receptors in the form of lipid nanoparticles, liposomes or micelles, including drugs or oligonucleotides.

Inventors

  • LI SHENGRONG
  • B. ROY
  • A. Druckitz

Assignees

  • 阿凡提极性脂质有限责任公司

Dates

Publication Date
20260512
Application Date
20241008
Priority Date
20231010

Claims (17)

  1. 1. A compound comprising structure (I), (II), (III) or (IV), or a combination of any two or more thereof: (I) (II) (III) (IV), Wherein: Each R 1 is independently selected from aliphatic alkyl C 4 -C 100 groups optionally substituted with one or more of alkenyl, alkynyl, hydroxy, amide, ester, and/or ether groups; R 2 is selected from [ -OCH 2 CH 2 -] p ,[-OCH 2 CH 2 -] p -O-, or ; R 3 is selected from formula (V) and formula (VI), formula (VE) and formula (VIE): (V) (VI) (VE) (VIE) m + is selected from alkali metal ions, alkaline earth metal ions, or primary, secondary, or tertiary ammonium ions; m, p and s are independently selected from integers of 1 to 120, And wherein E is an optional spacer or extender group.
  2. 2. The compound according to claim 1, wherein the compound comprises up to 15N-acetylgalactosamine moieties per molecule.
  3. 3. A compound according to claim 1 or 2, wherein R 1 is an unsubstituted aliphatic alkyl C 4 -C 100 group.
  4. 4. A compound according to any one of claims 1-3, wherein R 2 is [ -OCH 2 CH 2 -] p or [ -OCH 2 CH 2 -] p -O-.
  5. 5. A compound according to any one of claims 1-3, wherein R 2 is 。
  6. 6. A compound according to any one of claims 1-5, wherein p is an integer selected from 10 to 80, preferably 20 to 70, more preferably 30 to 60, most preferably 40 to 50.
  7. 7. A compound according to any one of claims 1-5, wherein s is an integer selected from 10 to 80, preferably 20 to 70, more preferably 30 to 60, most preferably 40 to 50.
  8. 8. A compound according to any one of claims 1-7, wherein m is an integer selected from 1 to 50, preferably 1 to 20, more preferably 1 to 10, most preferably 2 to 5.
  9. 9. The compound according to any one of claims 1-8, further comprising a spacer or extender group (E), wherein E has the structure: , wherein n is an integer between the values 0 to 6 and X is an alkyl chain of 0 to 4 carbons in length.
  10. 10. The compound according to claim 9 comprising the structure (IE), (IIE), (IIIE) or (IVE), or a combination of any two or more thereof: (IE) (IIE) (IIIE) (IVE)。
  11. 11. A compound according to claim 9 or 10, wherein R 3 according to claim 1 necessarily comprises a spacer or extender group (E), whereby R 3 is selected from formula (VE) and formula (VIE): (VE) (VIE)。
  12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, an active pharmaceutical ingredient and a pharmaceutically acceptable carrier.
  13. 13. A therapeutic agent targeting hepatic asialoglycoprotein receptor comprising a pharmaceutical oligonucleotide, antibody, enzyme, protein, small molecule or nucleotide, in the form of a lipid nanoparticle, or in the form of a liposome, or in the form of a micelle, comprising a compound according to any of claims 1 to 11.
  14. 14. The therapeutic agent for hepatic desialylated glycoprotein receptor according to claim 13, wherein the drug comprises at least one of a drug for bile acid synthesis disorder, a drug for cholestasis pruritus in Ala Ji Zeng syndrome, a drug for liver tumor, a drug for hepatic coma, a drug for hyperbilirubinemia, a drug for liver cirrhosis, a drug for liver metastasis in adenocarcinoma, a drug for metabolic dysfunction-related fatty liver disease, a drug for exocrine pancreatic dysfunction, a drug for portal hypertension, or a drug for progressive familial intrahepatic cholestasis.
  15. 15. The hepatic asialoglycoprotein receptor-targeting therapeutic agent according to claim 12 or 13, wherein the oligonucleotide comprises at least one of ABE (adenine base editor), miRNA inhibitor, antisense oligonucleotide, ribozyme, deoxyribozyme, plasmid, immunostimulatory nucleic acid, miRNA antagonist, anti-miRNA molecule, mimetic, super-active miRNA, and aptamer, allele-specific oligonucleotide, antisense oligonucleotide, ribonucleoprotein (RNP), mRNA, siRNA, sgRNA, gRNA, ss-siRNA, or a combination thereof.
  16. 16. A pharmaceutical composition comprising a therapeutic agent that targets hepatic asialoglycoprotein receptor according to any of claims 13 to 15 and a pharmaceutically acceptable carrier.
  17. 17. A method of treatment comprising administering to a patient in need thereof a therapeutic agent or pharmaceutical composition according to any one of claims 12 to 16 that targets hepatic asialoglycoprotein receptor.

Description

Lipid targeting hepatic asialoglycoprotein receptor and uses thereof Technical Field The present invention relates to lipids comprising N-acetylgalactosamine targeting hepatic asialoglycoprotein receptors. Background Compounds containing an N-acetylgalactosamine moiety are known to bind to hepatic asialoglycoprotein receptor (ASGR). However, these compounds are generally quite hydrophobic and thus less effective for delivering drugs or oligonucleotides to a person in need thereof. H. ACS Omega 2021, 6, 16259-16265 provided a review of liver-targeted delivery of N-acetylgalactosamine conjugated oligonucleotides. K. Godbout et al, pharmaceuticals 2022, 14, 2129 provide an overview of gene therapy by delivery of RNA to specific organs via lipid nanoparticles. L.N. Kasiewicz et al Nature Communications, (2023) 14:2776 discloses GalNAc-lipid nanoparticles that enable LDLR (low density lipoprotein receptor) independent liver delivery for CRISPR base editing therapies. Y.Zhou et al ACS cent Sci.2021, 7, 499-506, disclose that triple antenna (TRIANTENNARY) N-acetylgalactosamine conjugates act as degradation products for extracellular proteins. CA 02930393 A1 discloses that carbohydrate conjugates act as delivery reagents for oligonucleotides. The present disclosure provides lipid compounds targeting hepatic asialoglycoprotein receptors that contain a hydrophilic linker moiety that overcomes certain drawbacks associated with hydrophobic lipid moieties. These compounds provide a means of delivering therapeutic drugs or oligonucleotides to the liver via the hepatic asialoglycoprotein receptor. Summary of The Invention The present disclosure relates to lipid compounds that bind to three N-acetylgalactosamine units. The lipid compounds target hepatic asialoglycoprotein receptors and are useful for delivering therapeutic agents such as drugs or oligonucleotides to humans in need thereof. According to a specific embodiment, the lipid compound is used to form lipid nanoparticles that deliver therapeutic agents such as drugs or oligonucleotides to a person in need thereof. According to yet another embodiment, the lipid compound is used to form liposomes that deliver a therapeutic agent such as a drug or oligonucleotide to a person in need thereof. According to yet another embodiment, the lipid compound is used to form micelles, which deliver a therapeutic agent such as a drug or an oligonucleotide to a person in need thereof. According to an embodiment, the compound has structure (I), (II), (III), or (IV), or a combination of any two or more thereof. (I) (II) (III) (IV) In these structures (I), (II), (III) and (IV), each R 1 is independently selected from an aliphatic alkyl C 4-C100 group, optionally substituted with one or more of alkenyl, alkynyl, hydroxy, amide, ester and/or ether groups; R 2 is selected from [ -OCH 2CH2-]p,[-OCH2CH2-]p -O-, or ; R 3 is selected from formula (V) and formula (VI): (V) (VI); m + is selected from alkali metal ions, alkaline earth metal ions, or primary, secondary or tertiary ammonium ions, and M, p and s are independently selected from integers of 1 to 120. According to an embodiment, the compound having structure (I), (II), (III) or (IV) has no more than 3,5,7,9,11,13 or 15 moieties of structure (VI). In other words, the compound having structure (I), (II), (III) or (IV) has no more than 3,5,7,9,11,13 or 15N-acetylgalactosamine moieties per molecule. Therapeutic agents are provided that target hepatic asialoglycoprotein receptors comprising a drug or oligonucleotide in a lipid nanoparticle, liposome or micelle, including compounds having structures (I), (II), (III) or (IV) or a combination of any two or more thereof. Also provided are methods of treatment comprising administering to a patient in need thereof a therapeutic agent that targets hepatic asialoglycoprotein receptor. Drawings The figures show high performance liquid chromatograms of compounds according to embodiments of the present invention. Detailed Description Definition of the definition As used herein, the terms "prevention", "inhibition (suppress)" and "inhibition (suppressing)" refer to an action regimen (such as administration of a compound or pharmaceutical composition) initiated prior to the onset of a symptom, aspect or feature of a disease or condition that is intended to prevent or reduce the symptom, aspect or feature. The prevention and inhibition need not be to an absolute extent to be useful. As used herein, the terms "treatment", "treatment" and "treatment" as used herein refer to a regimen of action (such as administration of a compound or pharmaceutical composition) initiated after the onset of a symptom, aspect or feature of a disease or condition that is intended to eliminate or reduce the symptom, aspect or feature. The treatment need not be to an absolute extent in order to be useful. As used herein, the term "in need of treatment" as used herein refers to the judgment made by the caregiver that the patien