WO2023093807A1 - Composé et méthode de traitement de maladies hépatiques - Google Patents

Composé et méthode de traitement de maladies hépatiques Download PDF

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WO2023093807A1
WO2023093807A1 PCT/CN2022/134042 CN2022134042W WO2023093807A1 WO 2023093807 A1 WO2023093807 A1 WO 2023093807A1 CN 2022134042 W CN2022134042 W CN 2022134042W WO 2023093807 A1 WO2023093807 A1 WO 2023093807A1
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liver
inhibitor
pkd1
pharmaceutical composition
cid755673
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PCT/CN2022/134042
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English (en)
Chinese (zh)
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赵扬
林鹏燕
刘洋
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南京昕瑞再生医药科技有限公司
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Publication of WO2023093807A1 publication Critical patent/WO2023093807A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of biomedicine, in particular to compounds and methods for treating liver diseases.
  • the liver is an important vital organ in animals with metabolic functions as its main function. It regulates a variety of physiological functions, including detoxification, storage of liver glycogen, synthesis of secretory proteins, and production of bile.
  • the liver itself has a strong ability to regenerate. After a normal liver undergoes two-thirds partial hepatectomy, the remaining mature hepatocytes can proliferate rapidly and completely replace and restore the volume and function of the missing liver.
  • liver diseases including hepatitis, liver cirrhosis, liver cancer, liver metabolic diseases and liver failure, the liver gradually loses its ability to regenerate, which leads to a continuous decline in its physiological functions and ultimately endangers people's health and life.
  • WHO World Health Organization
  • the AMPK agonist is selected from: ETC-1002 or a structural analog thereof, A-769662 or a structural analog thereof, or a combination thereof.
  • the PKD1/2/3 inhibitor is CID755673 or a structural analog thereof.
  • the present invention provides the use of the organ preservation solution of the present invention for preserving isolated liver tissue or liver organ.
  • FIG. 5 shows the phase contrast images of cells cultured to the 7th day under the test conditions of Base2-based medium, presence or absence of SB431542, and addition of different small molecules. This experiment further proves that the small molecules ETC-1002, CID755673 and A-769662 can promote the proliferation of liver cells.
  • Fig. 6 shows that under each test condition with Base2 as the basal medium, the cell number statistics of the cells cultured to the 10th day. This experiment proves that the small molecules ETC-1002, CID755673 and A-769662 can promote the proliferation of liver cells.
  • Figure 8 Schematic diagram of the modeling of chronic liver fibrosis induced by 10% CCl 4 , and a schematic diagram of the administration window.
  • the AMPK agonist is selected from: ETC-1002 or a structural analog thereof, A-769662 or a structural analog thereof, or a combination thereof.
  • the method further comprises administering to the subject a therapeutically effective amount of another liver disease therapeutic agent.
  • the other liver disease treatment is a liver injury treatment.
  • the other liver disease therapeutic agent is acetylcysteine.
  • the AMPK agonists, PKD1/2/3 inhibitors, TGF ⁇ inhibitors and other therapeutic agents for liver diseases are administered in combination, they can be administered to the subject simultaneously or sequentially.
  • each specific small molecule compound mentioned herein includes its pharmaceutically acceptable salt.
  • the chemical structures of small molecule compounds ETC-1002, A-769662, CID755673, SB431542 and TEW-7197 exemplified herein can be found in Table 4.
  • the present invention provides an AMPK agonist and/or a PKD1/2/3 inhibitor, preferably a PKD1/2/3 inhibitor, in the preparation of a pharmaceutical composition for preventing and/or treating liver disease in a subject use.
  • the pharmaceutical composition further comprises a TGF ⁇ inhibitor or is for administration in combination with a TGF ⁇ inhibitor.
  • the TGF ⁇ inhibitor is selected from SB431542, a structural analog thereof, TEW-7197, a structural analog thereof, or a combination thereof.
  • the pharmaceutical composition further includes or is for administration in combination with other liver disease therapeutic agents.
  • the other liver disease treatment is a liver injury treatment.
  • the other liver disease therapeutic agent is acetylcysteine.
  • the present invention provides a pharmaceutical composition for preventing and/or treating liver disease in a subject, comprising a therapeutically effective amount of an AMPK agonist and/or a PKD1/2/3 inhibitor, preferably a PKD1/2/3 inhibitor 2/3 inhibitors, and a pharmaceutically acceptable carrier.
  • the AMPK agonist is selected from: ETC-1002 or a structural analog thereof, A-769662 or a structural analog thereof, or a combination thereof.
  • the PKD1/2/3 inhibitor is CID755673 or a structural analog thereof.
  • the pharmaceutical composition further comprises a therapeutically effective amount of a TGF ⁇ inhibitor.
  • the TGF ⁇ inhibitor is selected from SB431542, a structural analog thereof, TEW-7197, a structural analog thereof, or a combination thereof.
  • liver disease is drug-induced liver injury.
  • the liver disease is acetaminophen (APAP)-induced liver injury.
  • the liver disease is liver fibrosis.
  • terapéuticaally effective amount refers to an amount of a substance, compound, material, or composition comprising a compound that is at least sufficient to produce a therapeutic effect when administered to a subject. Thus, it is the amount necessary to prevent, cure, ameliorate, arrest or partially arrest the symptoms of a disease or disorder. For example, if a given clinical treatment that reduces a measurable parameter associated with a disease by at least 25% is considered to be an effective treatment, then a therapeutically effective amount of the drug used to treat the disease is necessary to reduce the parameter by at least 25% quantity.
  • the AMPK agonist is dosed at 0.1-200 mg/kg body weight, such as 1-200 mg/kg body weight, 1-150 mg/kg body weight, 1-100 mg/kg body weight, 1-50 mg/kg body weight, 1 - Administration at a dose of 30 mg/kg body weight, 1-20 mg/kg body weight, 1-15 mg/kg body weight, 1-10 mg/kg body weight, 1-5 mg/kg body weight or 3-5 mg/kg body weight.
  • the TGF ⁇ inhibitor is dosed at 0.1-200 mg/kg body weight, such as 1-200 mg/kg body weight, 1-150 mg/kg body weight, 1-100 mg/kg body weight, 1-50 mg/kg body weight, 1 - Administration at a dose of 30 mg/kg body weight, 1-20 mg/kg body weight, 1-15 mg/kg body weight, 1-10 mg/kg body weight, 1-5 mg/kg body weight or 3-5 mg/kg body weight.
  • said other therapeutic agent for liver diseases such as acetylcysteine
  • said other therapeutic agent for liver diseases is administered at 0.1-200 mg/kg body weight, such as 1-200 mg/kg body weight, 1-150 mg/kg body weight, 1-100 mg/kg body weight, Dose of 1-50 mg/kg body weight, 1-30 mg/kg body weight, 1-20 mg/kg body weight, 1-15 mg/kg body weight, 1-10 mg/kg body weight, 1-5 mg/kg body weight or 3-5 mg/kg body weight apply.
  • the other liver disease therapeutic agent such as acetylcysteine
  • the compounds or pharmaceutical compositions of the present invention can be administered by any suitable method known to those of ordinary skill in the art, for example, intravenously, intramuscularly, intraperitoneally, intracerebrospinally, subcutaneously, intraarticularly, intrasynovially, Administration by intrathecal, oral, topical or inhalation routes.
  • the preferred methods of preparation are vacuum drying or freeze-drying techniques which yield the active ingredient from a previously sterile-filtered liquid medium. Add powders of any other desired ingredients.
  • the liquid medium should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose prior to injection.
  • Preparation of highly concentrated compositions for direct injection is also contemplated, where use of DMSO as a solvent would conceivably result in extremely rapid penetration, delivering high concentrations of active agent to small areas.
  • said isolated liver tissue or liver organoid with at least one compound for a period of time, wherein said at least one compound comprises an AMPK agonist and/or a PKD1/2/3 inhibitor, preferably PKD1/2/3 Inhibitors.
  • the AMPK agonist is selected from: ETC-1002 or a structural analog thereof, A-769662 or a structural analog thereof, or a combination thereof.
  • the concentration of the AMPK agonist is from about 0.01 ⁇ M to about 50 ⁇ M, such as about 0.01 ⁇ M, about 0.1 ⁇ M, about 1 ⁇ M, about 2 ⁇ M, about 3 ⁇ M, about 4 ⁇ M, about 5 ⁇ M, about 7.5 ⁇ M, about 10 ⁇ M, About 15 ⁇ M, about 20 ⁇ M, about 30 ⁇ M, about 40 ⁇ M, about 50 ⁇ M.
  • the isolated liver tissue or liver organ is, for example, liver tissue or liver organ that has been removed from a donor subject and is to be transplanted into a recipient subject.
  • the method of the invention can maintain or enhance the liver function and reduce the damage of liver tissue or liver organ.
  • Said period of time is, for example, the period of time during which said liver tissue or liver organ is removed from the donor until transplanted into the recipient.
  • the methods of the present invention can prolong the storage time of the liver tissue or liver organoid in vitro.
  • Example 1 Small molecules ETC-1002, CID755673, and A-769662 can promote the expansion of human hepatocytes in basal medium Base1
  • FIG. 1 The experimental scheme for testing the effect of small molecule compounds on the expansion of human hepatocytes is shown in Figure 1. Specifically, after thawing frozen primary human hepatic parenchymal cells, they were resuspended in DMEM+10% FBS medium, and inoculated on well plates pre-coated with Type I collagen at a density of 2.5 ⁇ 10 5 /cm 2 superior. After the cells adhered to the wall, the original medium was sucked off immediately, and replaced with a test medium with different conditions. After 7 days of culture, the cell state was identified by immunofluorescence of Albumin and SOX9, and the cells were counted after 10 days of culture.
  • ACL adenosine triphosphate-citrate lyase
  • AMPK adenylate-activated protein kinase
  • ETC-1002 is a prodrug in an inactive state that is converted to an ACL inhibitor in vivo by endogenous hepatic ACS activity (activated state, ECT-1002-CoA). ETC-1002 has not been reported to promote hepatocyte expansion.
  • Example 2 small molecules ETC-1002, CID755673, and A-769662 can promote the expansion of human hepatocytes in the basal medium Base2
  • Basal medium Base2 refers to Zhang, K. et al. In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity. Cell Stem Cell 23, 806-+, doi:10.1016/j.stem.2018.10.018 (2016). The specific components are shown in Table 2 below.
  • Carbon tetrachloride (CCl 4 ) has been widely used for experimental liver injury in rodents.
  • a single dose of CCl 4 can cause central area necrosis and steatosis, while long-term use can cause liver fibrosis, cirrhosis and liver cancer (Scholten, D., Trebicka, J., Liedtke, C. & Weismün, R.
  • Example 4 Candidate small molecules ETC-1002 and CID755673 can effectively treat chronic liver injury
  • TEW-7197 (Vactosertib) is a highly potent, selective, orally bioavailable TGF- ⁇ receptor ALK4/ALK5 inhibitor with IC50 of 13nM and 11nM, respectively.
  • the TGF- ⁇ pathway is considered in the art as an important factor involved in liver fibrosis, and is also one of the important targets for the treatment of liver fibrosis and liver injury.
  • Example 1 the therapeutic effects of candidate small molecules ETC-1002 and CID755673 on chronic liver injury were tested, and TEW-7197 was used as a positive control.
  • the candidate small molecule and the control drug were administered daily: ETC-1002, 30 mg/kg/day orally; CID755673, 4.4 mg/kg/day intraperitoneally; TEW-7197, 2.5 mg/kg/day intraperitoneally. mg/kg/day.
  • Four weeks after administration the mice were sacrificed and samples were taken for analysis.
  • ETC-1002 or CID755673 treatment increases the number of SOX9 hepatic parenchymal cells
  • Sections were stained with Picro-Sirius red (Sirius red) solution (0.1% direct red 80plus 0.1% fast green dissolved in 1.2% saturated picric acid aqueous solution, both from Sigma-Aldrich) after dewaxing, and incubated for 60 minutes. Sections were rinsed with water, dehydrated, and loaded in xylene. Quantification of Sirius red staining was performed in a blinded manner using ImageJ software.
  • CID755763 Under the treatment of different concentrations of CID755763, it was analyzed that under the condition of 10uM-50uM, CID755673 maintained the epithelial-like morphology of hepatic parenchymal cells better after APAP injury ( Figure 12D), and it was found that CID755763 was in the In the case of 10uM-50uM, compared with the control group, it can significantly increase the proportion of surviving hepatic parenchymal cells and reduce the release of transaminases ALT and AST in the process of hepatic parenchymal necrosis (Fig. 12E-F).
  • Example 6 The effect of small molecule CID75573 on resisting the lethal injury induced by acetaminophen APAP in mice
  • mice of 12-16 weeks were injected intraperitoneally with 800 mg/kg APAP. All mice were fasted for 19 hours before APAP injection, and continued to fast for 4 hours after APAP injection.
  • Set 10 mice each in the control group and the treatment group, and the treatment group began to perform intraperitoneal injection of CID 755673 1 hour after APAP injection, wherein the dosage of CID755673 was 30 mg/kg.
  • the control group was injected with corresponding drug solvent 2%DMSO+5%Tween80+30%PEG+63%H2O. Afterwards, the survival of the mice was observed for a long time ( FIG. 13A ). It was found that the CID755673 30mg/kg administration group could significantly improve the survival rate of mice in the lethal injury induced by APAP compared with the vehicle control group ( Figure 13B).
  • mice of 8-10 weeks were also injected intraperitoneally with 500 mg/kg APAP, and all mice were fasted for 16 hours before APAP injection.
  • the control group was injected with corresponding drug solvent 2%DMSO+5%Tween80+30%PEG+63%H2O. 24 hours after APAP injection, the levels of transaminase ALT and AST were detected and the area of liver necrosis was counted ( FIG. 13C ).
  • Example 7 the effect of small molecule ETC1002 on alleviating carbon tetrachloride CCl4 induced liver fibrosis in mice
  • Carboxymethylcellulose (CMC) and Tween-20 were added to make a final solution containing 0.5% CMC and 0.025% Tween with a final pH of 7-8.
  • the compound concentration in the dosing solution was administered in a volume of 10 ml/kg body weight.
  • the administration group and the control group consisted of 6 mice respectively.
  • the serum was taken to fix liver samples, and HE staining and Sirius red staining were performed to clarify the proportion of fibrosis area.
  • Figure 14A The compound concentration in the dosing solution was administered in a volume of 10 ml/kg body weight.
  • the administration group and the control group consisted of 6 mice respectively.
  • the serum was taken to fix liver samples, and HE staining and Sirius red staining were performed to clarify the proportion of fibrosis area.
  • Figure 14A The proportion of fibrosis area.

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Abstract

La présente invention concerne un composé et une méthode de traitement de maladies hépatiques.
PCT/CN2022/134042 2021-11-24 2022-11-24 Composé et méthode de traitement de maladies hépatiques WO2023093807A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101054356A (zh) * 2006-04-13 2007-10-17 邵长青 用于祛痰和治疗肝病的乙酰半胱氨酸钠及其制备方法
WO2020215034A1 (fr) * 2019-04-19 2020-10-22 The Regents Of The University Of California Axe ampk/caspase-6 contrôlant les lésions hépatiques dans la stéatohépatite non alcoolique
CN111971030A (zh) * 2018-02-16 2020-11-20 艾斯柏伦治疗公司 贝派地酸的缓释制剂
CN112843253A (zh) * 2021-01-13 2021-05-28 上海交通大学 一种基因/药物复合脂质制剂及其制备方法和用途
US20210205286A1 (en) * 2019-12-30 2021-07-08 Unm Rainforest Innovations Methods and Compositions for Treating Autophagy Related Disease States and Conditions Utilizing AMPK Activation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101054356A (zh) * 2006-04-13 2007-10-17 邵长青 用于祛痰和治疗肝病的乙酰半胱氨酸钠及其制备方法
CN111971030A (zh) * 2018-02-16 2020-11-20 艾斯柏伦治疗公司 贝派地酸的缓释制剂
WO2020215034A1 (fr) * 2019-04-19 2020-10-22 The Regents Of The University Of California Axe ampk/caspase-6 contrôlant les lésions hépatiques dans la stéatohépatite non alcoolique
US20210205286A1 (en) * 2019-12-30 2021-07-08 Unm Rainforest Innovations Methods and Compositions for Treating Autophagy Related Disease States and Conditions Utilizing AMPK Activation
CN112843253A (zh) * 2021-01-13 2021-05-28 上海交通大学 一种基因/药物复合脂质制剂及其制备方法和用途

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