WO2023221361A1 - Utilisation d'un inhibiteur à petites molécules bay87-2243 dans la préparation d'un médicament pour traiter l'hépatite b - Google Patents
Utilisation d'un inhibiteur à petites molécules bay87-2243 dans la préparation d'un médicament pour traiter l'hépatite b Download PDFInfo
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- WO2023221361A1 WO2023221361A1 PCT/CN2022/121759 CN2022121759W WO2023221361A1 WO 2023221361 A1 WO2023221361 A1 WO 2023221361A1 CN 2022121759 W CN2022121759 W CN 2022121759W WO 2023221361 A1 WO2023221361 A1 WO 2023221361A1
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- bay87
- drug
- hepatitis
- hbv
- cells
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- CDJNNOJINJAXPV-UHFFFAOYSA-N 5-[1-[[2-(4-cyclopropylpiperazin-1-yl)pyridin-4-yl]methyl]-5-methylpyrazol-3-yl]-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole Chemical compound CC1=CC(C=2ON=C(N=2)C=2C=CC(OC(F)(F)F)=CC=2)=NN1CC(C=1)=CC=NC=1N(CC1)CCN1C1CC1 CDJNNOJINJAXPV-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000003814 drug Substances 0.000 title claims abstract description 31
- 229940079593 drug Drugs 0.000 title claims abstract description 31
- 239000003112 inhibitor Substances 0.000 title claims abstract description 14
- 150000003384 small molecules Chemical class 0.000 title claims abstract description 11
- 208000006454 hepatitis Diseases 0.000 title 1
- 231100000283 hepatitis Toxicity 0.000 title 1
- 241000700721 Hepatitis B virus Species 0.000 claims abstract description 54
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 14
- 238000013518 transcription Methods 0.000 claims abstract description 12
- 230000035897 transcription Effects 0.000 claims abstract description 12
- 108091036055 CccDNA Proteins 0.000 claims abstract 2
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- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 claims 1
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 46
- 230000010076 replication Effects 0.000 abstract description 9
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- YTRQFSDWAXHJCC-UHFFFAOYSA-N chloroform;phenol Chemical compound ClC(Cl)Cl.OC1=CC=CC=C1 YTRQFSDWAXHJCC-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
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- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
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- 230000007882 cirrhosis Effects 0.000 description 1
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- 235000021266 loss of appetite Nutrition 0.000 description 1
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Images
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
Definitions
- the present invention relates to the use of small molecule inhibitor BAY87-2243 in preparing drugs for treating hepatitis B
- Viral hepatitis B (viral hepatitis type B) is an infectious disease caused mainly by liver lesions caused by hepatitis B virus (HBV).
- HBV hepatitis B virus
- the main clinical manifestations are loss of appetite, nausea, upper abdominal discomfort, liver pain, and fatigue. Some patients may have jaundice, fever and hepatomegaly accompanied by liver function damage. Some patients can become chronic and even develop cirrhosis, and a few can develop liver cancer.
- nucleoside (acid) analogues and interferons have very limited effects in treating chronic HBV infection, and only a few patients can achieve "functional cure.”
- the key to achieving a cure for chronic hepatitis B virus infection is to completely eliminate covalently closed circular DNA (cccDNA) in the host liver cells. It is the template for HBV transcription and replication and the viral gene reservoir. It is also the key to the recurrence of chronic hepatitis B patients after drug withdrawal. inducement.
- cccDNA covalently closed circular DNA
- the small molecule inhibitor BAY87-2243 is a potent and selective hypoxia-inducible factor-1 (HIF-1) inhibitor. There are currently reports that it inhibits tumor cell proliferation by interfering with mitochondrial function and can be used to treat cancers such as lung cancer. There are also reports that it has a positive impact on the intestinal mucosal barrier (IMB) function and can be used to treat sepsis. There are currently no reports of BAY87-2243 being used to treat hepatitis B.
- IMB intestinal mucosal barrier
- the present invention provides the use of the small molecule inhibitor BAY87-2243 in the preparation of drugs for treating hepatitis B; the BAY87-2243 is a specific inhibitor of HIF-1.
- the drug is a drug that reduces the production level of hepatitis B surface antigen.
- the drug is a drug that reduces the production level of hepatitis B e antigen.
- the drug is a drug that inhibits the transcription of hepatitis B virus.
- the drug is a drug that inhibits hepatitis B virus DNA replication.
- the drug is a drug that reduces the expression level of hepatitis B virus cccDNA.
- the drug is a preparation prepared by using the small molecule inhibitor BAY87-2243 as the active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.
- the preparation is an oral preparation; the oral preparation is granules, solutions, pills, ointments or tablets.
- the small molecule inhibitor BAY87-2243 can significantly inhibit HBV transcription and replication, and effectively reduce the expression level of cccDNA, so as to completely eliminate hepatitis B.
- the patient's virus-carrying status becomes possible, and the goal of antiviral treatment is finally achieved, which has the prospect of practical promotion and application.
- FIG. 1 Statistical chart of research data of BAY87-2243 treatment on HBsAg/HBeAg secretion (A: Effects of different concentrations of BAY87-2243 treatment on HepAD38 cytotoxicity and HBsAg secretion, B: Different concentrations of BAY87-2243 treatment on HepG2.2.15 cytotoxicity and HBsAg secretion) Effect of HBsAg secretion, C: Effect of different concentrations of BAY87-2243 treatment on HepAD38 cytotoxicity and HBeAg secretion, D: Effect of different concentrations of BAY87-2243 treatment on HepG2.2.15 cytotoxicity and HBeAg secretion)
- FIG. 2 Statistical chart of research data on the effects of BAY87-2243 treatment on HBV transcription and replication levels and HBV cccDNA expression levels (A: The effect of BAY87-2243 treatment on the expression level of HBV total RNA in HepAD38 cells, B: The effect of BAY87-2243 treatment on the expression level of HBV in HepAD38 cells Effect of HBVpgRNA expression level in cells, C: Effect of BAY87-2243 treatment on HBVDNA replication level in HepAD38 cells, D: Effect of BAY87-2243 treatment on HBVcccDNA expression level in HepAD38 cells)
- FIG. 3 Statistical diagram of the effect of BAY87-2243 treatment on HBV transcription and replication levels and HBV cccDNA expression levels in HBV-infected human primary hepatocytes (A: Effect of BAY87-2243 treatment on HBsAg secretion, B: BAY87-2243 The effect of treatment on HBeAg secretion, C: The effect of BAY87-2243 treatment on the expression level of HBV total RNA, D: The effect of BAY87-2243 treatment on the expression level of HBVpgRNA, E: The effect of BAY87-2243 treatment on the expression level of intracellular HBV DNA, F: Effect of BAY87-2243 treatment on intracellular HBV cccDNA expression level)
- hepatitis B virus surface antigen diagnostic kit enzyme-linked immunoassay; Shanghai Kehua, SI0910113
- hepatitis B virus E antigen detection kit enzyme-linked immunoassay; Shanghai Kehua, 20163400144
- the specific microplate reader test results and ELISA kit test results are shown in Figure 1A-D.
- BAY87-2243 has little effect on cytotoxicity at a concentration of 100nM, and BAY87-2243 at a lower concentration ( ⁇ 0.1nM) can effectively inhibit the secretion of HBsAg and HBeAg.
- the present invention has proven through a series of experiments that the small molecule inhibitor BAY87-2243 can significantly inhibit HBV transcription and replication, and effectively reduce the expression level of cccDNA, making it possible to completely eliminate the virus-carrying status of hepatitis B patients, and ultimately achieve the goal of antiviral treatment. , with practical promotion and application prospects.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Biotechnology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne l'utilisation d'un inhibiteur à petites molécules BAY87-2243 dans la préparation d'un médicament pour traiter une infection par le virus de l'hépatite B. Selon la présente invention, à l'aide de différentes lignées cellulaires d'hépatome produisant de manière stable le virus de l'hépatite B (VHB) ou d'hépatocytes primaires humains infectés par le VHB à soumettre à des expériences de traitement in vitro selon différentes concentrations de BAY87-2243, il est prouvé que BAY87-2243 peut inhiber considérablement la transcription et la réplication du VHB et réduire efficacement le niveau d'expression d'ADN circulaire.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210529236.9 | 2022-05-16 | ||
| CN202210529236 | 2022-05-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023221361A1 true WO2023221361A1 (fr) | 2023-11-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2022/121759 WO2023221361A1 (fr) | 2022-05-16 | 2022-09-27 | Utilisation d'un inhibiteur à petites molécules bay87-2243 dans la préparation d'un médicament pour traiter l'hépatite b |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN114886895B (fr) |
| WO (1) | WO2023221361A1 (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114886895B (zh) * | 2022-05-16 | 2023-02-03 | 重庆医科大学 | 小分子抑制剂bay87-2243在制备治疗乙型肝炎的药物中的用途 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381463A (zh) * | 2017-08-08 | 2019-02-26 | 复旦大学 | 他扎罗汀在制备治疗乙肝病毒感染药物中的应用 |
| WO2019043193A1 (fr) * | 2017-09-01 | 2019-03-07 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Inhibiteur destiné à être utilisé dans la prévention et/ou le traitement d'une infection par le virus de l'hépatite b |
| CN113337602A (zh) * | 2020-03-02 | 2021-09-03 | 苏州亚盛药业有限公司 | Mdm2抑制剂的治疗方法和生物标志物 |
| WO2022093770A1 (fr) * | 2020-10-27 | 2022-05-05 | Memorial Sloan Kettering Cancer Center | Polythérapie à l'aide d'inhibiteurs de pi3k-akt-mtor et d'agents induisant la ferroptose pour traiter un cancer |
| CN114886895A (zh) * | 2022-05-16 | 2022-08-12 | 重庆医科大学 | 小分子抑制剂bay87-2243在制备治疗乙型肝炎的药物中的用途 |
-
2022
- 2022-05-25 CN CN202210576920.2A patent/CN114886895B/zh active Active
- 2022-09-27 WO PCT/CN2022/121759 patent/WO2023221361A1/fr unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109381463A (zh) * | 2017-08-08 | 2019-02-26 | 复旦大学 | 他扎罗汀在制备治疗乙肝病毒感染药物中的应用 |
| WO2019043193A1 (fr) * | 2017-09-01 | 2019-03-07 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Inhibiteur destiné à être utilisé dans la prévention et/ou le traitement d'une infection par le virus de l'hépatite b |
| CN113337602A (zh) * | 2020-03-02 | 2021-09-03 | 苏州亚盛药业有限公司 | Mdm2抑制剂的治疗方法和生物标志物 |
| WO2022093770A1 (fr) * | 2020-10-27 | 2022-05-05 | Memorial Sloan Kettering Cancer Center | Polythérapie à l'aide d'inhibiteurs de pi3k-akt-mtor et d'agents induisant la ferroptose pour traiter un cancer |
| CN114886895A (zh) * | 2022-05-16 | 2022-08-12 | 重庆医科大学 | 小分子抑制剂bay87-2243在制备治疗乙型肝炎的药物中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114886895B (zh) | 2023-02-03 |
| CN114886895A (zh) | 2022-08-12 |
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