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WO2021253647A1 - Utilisation d'un inhibiteur de petites molécules dans le traitement de la pneumonie virale respiratoire - Google Patents

Utilisation d'un inhibiteur de petites molécules dans le traitement de la pneumonie virale respiratoire Download PDF

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Publication number
WO2021253647A1
WO2021253647A1 PCT/CN2020/113478 CN2020113478W WO2021253647A1 WO 2021253647 A1 WO2021253647 A1 WO 2021253647A1 CN 2020113478 W CN2020113478 W CN 2020113478W WO 2021253647 A1 WO2021253647 A1 WO 2021253647A1
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Prior art keywords
virus
ahr
inhibitor
ido
combination
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Chinese (zh)
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黄波
刘玉英
佟伟民
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Institute of Basic Medical Sciences of CAMS and PUMC
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Institute of Basic Medical Sciences of CAMS and PUMC
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    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • This application relates to the fields of biology, medicine and clinical. Specifically, it relates to small molecule inhibitors and their use in the treatment of viral pneumonia.
  • Viral pneumonia can break out or spread. Viral pneumonia can occur at any time of the year, but it is more common in winter and spring. Initially, the above-mentioned respiratory tract virus infection is the main cause, and as the virus spreads down to the lungs, it causes pneumonia.
  • Viral pneumonia can be transmitted through droplets.
  • the clinical manifestations are generally mild, mainly with similar symptoms of respiratory diseases such as headache, fatigue, fever, and cough.
  • Respiratory tract infection is one of the leading causes of death in the world, especially patients with severe pneumonia have high mortality and serious sequelae.
  • viruses such as influenza virus and coronavirus are the main pathogens that cause regional outbreaks of severe pneumonia, which are highly infectious and have a high fatality rate.
  • an AhR (arylhydrocarbon receptor) inhibitor which can be used as a viral pneumonia preparation.
  • the viral pneumonia preparation contains an AhR inhibitor.
  • the term "inhibitor” refers to a natural compound or a synthetic compound that inhibits (or reduces or down-regulates) the expression of genes and/or proteins, and/or inhibits (or reduces or down-regulates) genes and/or The activity of the protein and/or regulate the signal transduction pathway related to the gene and/or protein.
  • the inhibitor can act on any of the following links or combinations of genes and/or proteins: such as but not limited to translation, post-translational processing, stability, degradation, nuclear localization, cytoplasmic localization, transcription , Post-transcriptional processing, activation, inactivation, modification, signal transduction. Inhibitors are allowed to be competitive, non-competitive, completely antagonistic, or partially antagonistic.
  • an AhR inhibitor refers to a compound that has the following effects: inhibits (or reduces or down-regulates) the expression of the gene encoding AhR, and/or the expression of AhR, and/or the activity of AhR, and/or modulates the signal transduction pathway related to AhR (For example, but not limited to upstream of AhR-related signaling pathways).
  • an AhR inhibitor in the preparation of a medicament, wherein the medicament is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia, or Its symptoms.
  • the virus is selected from one or a combination of: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza virus, Human metapneumovirus, Hendra virus, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof.
  • the drug is prepared into a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration.
  • AhR inhibitors suitable for the present disclosure include, but are not limited to, the compounds disclosed in the prior art: WO2019036657, WO2018195397, CN106860471A, WO2013034685, WO2012015914.
  • the AhR inhibitor is selected from one or a combination of the following: AhR antagonist 1, ⁇ -NF, CB7993113, CMLD-2166, CH223191, DMF, GNF351, PDM2, StemRegenin 1, SR1, IDO inhibitor.
  • an IDO (indoleamine 2,3-dioxygenase) inhibitor is provided, which can be used as a viral pneumonia preparation.
  • the viral pneumonia preparation contains an IDO inhibitor.
  • IDO is an active molecule located upstream of the AhR signaling pathway. Therefore, inhibitors acting on IDO can indirectly modulate the activity of AhR.
  • IDO inhibitors refer to compounds that have the following effects: inhibit (or reduce or down-regulate) the expression of IDO-encoding genes, and/or the expression of IDO, and/or the activity of IDO.
  • IDO inhibitors can generally be divided into the following types according to their structure:
  • An exemplary compound is the N-methyl derivative of tryptophan L1MT;
  • 4-benzimidazole and its derivatives can coordinate with the iron atom of heme and have strong IDO inhibitory activity.
  • An exemplary compound is NLG919 from NewLink Genetics;
  • N-Hydroxy amidine compounds can combine with the iron atom of heme and at the same time form a hydrogen bond with the nitrogen atom on the side amide group.
  • An exemplary compound is INCB024360.
  • IDO inhibitors suitable for the present disclosure include, but are not limited to, compounds disclosed in the prior art: CN106866648B, CN106883224B, CN107501272B, CN109438513B, CN109748838B, CN105567690B, CN107260743B, WO2015173764.
  • the IDO inhibitor is selected from one or a combination of the following: tryptophan analogs, quinone and its derivatives, imidazole and its derivatives, triazole and its derivatives, N -Hydroxyamidine and its derivatives.
  • the IDO inhibitor is selected from one or a combination of the following: 1-MT, Epacadostat, DO-IN-2, NLG919, PF-06840003, INCB024360, Exiguamine A, benzimidazole.
  • the amount of the AhR inhibitor in a unit formulation is 10 mg to 10 g.
  • the amount of IDO inhibitor in a unit formulation is 1 g to 10 g.
  • the amount of the AhR inhibitor in the unit formulation is 10 mg to 80 mg.
  • the coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof.
  • treatment is embodied as one or a combination selected from:
  • the viral pneumonia is selected from: mild, normal, severe, and critical.
  • a pharmaceutical composition comprising an AhR inhibitor, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is used for any one or a combination selected from the following: preventing the occurrence or recurrence of viral pneumonia, treating viral pneumonia or its symptoms.
  • the virus is selected from one or a combination of the following: coronavirus, influenza A virus, influenza B virus, influenza C virus, measles virus, mumps virus, respiratory syncytial virus, parainfluenza Virus, human metapneumovirus, Hendra virus, Nipa virus, rubella virus, rhinovirus, adenovirus, reovirus, Coxsackie virus, ECHO virus, and variants thereof.
  • the coronavirus is selected from: SARS, MERS, 2019-nCoV, and variants thereof.
  • the pharmaceutical composition is a dosage form selected from the group consisting of injections, sprays, aerosols, nasal drops, oral preparations, and dosage forms suitable for mucosal administration.
  • a method of preventing or treating viral pneumonia comprising administering a prophylactically effective amount or a therapeutically effective amount of an AhR inhibitor to a subject.
  • administration routes that may be mentioned include, but are not limited to: intramuscular, intravenous, subcutaneous, intradermal, oral, intranasal, respiratory, transmucosal, sublingual, parenteral.
  • effective amount refers to the amount of the drug, compound, or pharmaceutical composition necessary to obtain any one or more beneficial or desired therapeutic results.
  • beneficial or desired results include: improving clinical results (eg, reducing morbidity, mortality, improving one or more symptoms), reducing the severity, delaying the onset of the disease (including the disease or its complications, in the course of the development of the disease) Intermediate pathological phenotypes, biochemical, histological and/or behavioral symptoms presented in).
  • the unit preparation is a preparation that satisfies the active ingredient (AhR inhibitor) required for one-time administration, such as a unit (needle) injection or the like.
  • the amount of the drug required by the patient for one administration can be conveniently obtained by calculating the product of the patient's weight and the unit weight dose required for the patient's one administration.
  • the dosage can be determined initially by the equivalent dose conversion relationship between the unit weight dose of experimental animals and humans.
  • it can be based on the guidance provided by the FDA, SFDA and other drug regulatory agencies, and you can also refer to (Huang Jihan et al., "Equivalent dose conversion between animals and between animals and humans in pharmacological trials", “Chinese Clinical Pharmacology and Therapeutics” , 2004 Sep; 9(9): 1069-1072).
  • a conversion factor of 0.0026 according to the body surface area of humans and mice can be used to convert the doses of humans and mice.
  • the IDO inhibitor is administered to the mouse in an amount of 1000 mg/kg (for example, for a 20 g mouse, the IDO inhibitor is prepared as a 5 mg/mL solution with water , Mice are given 4 mL of the solution every day).
  • a method for preventing a patient with respiratory viral pneumonia from becoming severely ill including administering the anti-respiratory viral pneumonia preparation to a patient suffering from respiratory viral pneumonia or an individual with a tendency to become severely ill. the process of.
  • the specific procedure is intravenous or oral AhR inhibitor.
  • the amount of the AhR inhibitor in the anti-respiratory viral pneumonia preparation can be controlled as needed, so as to facilitate the administration to patients with viral pneumonia at different stages.
  • interferon is the first warning of virus invasion. Its signal activates a series of antiviral genes to exert a direct antiviral effect. However, the delayed interferon response may cause the body's immunopathological changes through the recruitment and activation of innate immune cells that produce high levels of inflammatory factors.
  • the applicant’s study found that IFN- ⁇ and IFN- ⁇ up-regulated the expression of mucin in BAES-2B cells, and the mucus produced was blocked in the patient’s alveolar cavity, which resulted in dyspnea and hypoxemia of the patient, leading to death of the patient.
  • AhR inhibitors effectively block the mucus produced by the respiratory system induced by IFN- ⁇ and IFN- ⁇ , and can achieve clinical treatment and prevention of critically ill patients with respiratory viral pneumonia virus pneumonia value.
  • the patient refers to a virus carrier, especially a patient who has or may have symptoms due to the presence of the virus.
  • patients are especially patients who are at risk of developing severe or critical illness.
  • Figure 1 shows the PAS staining experiment found that there may be a large amount of mucus-like substances in the alveolar lavage fluid of patients with new coronary disease.
  • Figure 2A and Figure 2B show the humanized ACE2 transgenic mice as the animal model of SARS-CoV-2 infection. Compared with the control group (Mock group, hACE2 mice not infected with the virus), the infected group mice The up-regulated expression and nuclear localization of AhR protein in lung epithelial cells (Figure 2A), and increased IFN- ⁇ expression in lung tissue was found in the infected group ( Figure 2B).
  • Figures 3A to 3E show that after bronchial nebulization treatment of mice with IFN- ⁇ or IFN- ⁇ , the lung function of the mice was found to be damaged. After intravenous injection of AhR inhibitor, the lung function of the mice returned to normal .
  • Fig. 4B shows that after intravenous injection of AhR inhibitor, the apparent increase in mucin levels in the lungs of mice was reversed.
  • FIGs 5A to 5F show that humanized ACE2 (hACE2) transgenic mice were used as the animal model of SARS-CoV-2 infection. Compared with the control group (Mock group-uninfected hACE2 mice), In the infected group, the expression levels of IFN- ⁇ and IFN ⁇ in the lung tissue were found to increase ( Figure 5A to Figure 5D). The expression of IFN- ⁇ at different time points was measured by real-time PCR ( Figure 5E). At different time points after hACE2 transgenic mice were infected with SARS-CoV-2, the expression of IFN- ⁇ was measured by real-time PCR (Figure 5F).
  • Figures 6A to 6C show (scale bar: 50 ⁇ m): SARS-CoV-2 infected humanized ACE2 transgenic mice were used as animal models, and it was observed that the administration of AhR inhibitors reversed the pneumonia symptoms of the infected mice.
  • Fig. 6A control group Fig. 6B model group
  • Fig. 6C treatment group Fig. 6A treatment group.
  • BEAS-2B human lung epithelial cell line was purchased from CCTCC of China Collection of Types;
  • SARS-CoV-2 comes from the Institute of Medical Laboratory Animals, Chinese Academy of Medical Sciences;
  • mice Female Balb/c mice aged 6-8 weeks were purchased from the Experimental Animal Center of Peking Union Medical College, Chinese Academy of Medical Sciences;
  • IDO inhibitor (1-MT) was purchased from SIGMA, USA;
  • AhR inhibitor (CH223191) was purchased from MCE Company, USA.
  • BAL samples from SARS-CoV-2 patients.
  • BAL samples come from 22-82-year-old patients, 4 males and 4 females.
  • the oxygen saturation is ⁇ 93%
  • ICU monitoring and treatment is required.
  • Example 1 SARS-COV-2 virus infection leads to the expression of a large number of mucins in the lung tissues of patients
  • the operation method is as follows: 2 hours before the operation, intramuscular injection of atropine and phenobarbital sodium, and local anesthesia with lidocaine hydrochloride 0.1g. Patients with poor compliance and anxiety are given intravenous painless anesthesia; after the anesthesia is completed, Olympus The electronic bronchoscope was inserted through the patient’s side of the nasal cavity to the lesion and lower respiratory tract secretions, and 50ml of sterile 0.9% sodium chloride solution was given for lavage or repeated lavage after brushing, and then the lavage fluid was collected and Put it into a sterile sputum collection bottle and send it for inspection within 2h.
  • the specimens submitted for inspection shall be separated and identified in accordance with the corresponding requirements of the "National Clinical Laboratory Procedures".
  • the isolated bronchoalveolar lavage fluid (BAL) specimens were fixed with 10% neutral formalin, embedded in paraffin, conventional HE staining, immunohistochemistry and PAS staining, and observed under light microscope.
  • PAS staining showed a large amount of mucus in the bronchoalveolar lavage fluid (BAL) ( Figure 1), and the results showed that viral infection caused the expression of a large amount of mucin in the lung tissue of patients with new coronary pneumonia.
  • SARS-COV-2 virus stimulates the nuclear localization phenomenon of AHR in lung tissue
  • C57-humanized ACE2 transgenic mice adopt non-exposure intratracheal injection method.
  • the animal was fully upright and rotated to make the drug evenly distributed in the lungs, and waited for 1 week for modeling.
  • Lung tissue collection After the mice were anesthetized with sodium barbital, the lung tissues were taken out after the mice were sacrificed, and the blood stains on the surface of the lung tissues were washed with preparatory normal saline. After the above operations were performed as quickly as possible, the tissues were then stored in the lungs. Store at -80°C. A part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for the preparation of immunofluorescence staining.
  • Example 3 AHR inhibitor reverses IFN- ⁇ or IFN- ⁇ causing lung function damage in mice
  • mice use non-exposure intratracheal injection.
  • the normal group was injected with the same amount of normal saline through the trachea at one time, and the experimental group was injected with 5 ⁇ g/mouse IFN- ⁇ or 10 ⁇ g/mouse IFN- ⁇ through the trachea. After the injection of the medicine, immediately rotate the animal upright to make the medicine evenly distributed in the lungs. The drug was administered once a day, and after four consecutive days of administration, blood gas analysis and lung function tests in mice were performed.
  • PBS PBS is given to the trachea every day
  • mice daily tracheal administration of 10 ⁇ g/mouse IFN- ⁇ +10mg/kg CH223191;
  • IFN- ⁇ and IFN- ⁇ can reduce the blood oxygen saturation of mice (Figure 3A), hypoxia and dyspnea, increase Rrs (respiratory system resistance), ERS (respiratory system elasticity), PV-k and Eta, etc.
  • the level of the index reflects the damage of lung function in mice.
  • Example 4 AHR inhibitor reverses IFN- ⁇ or IFN- ⁇ causing mucin up-regulation and lung function damage in mouse lung tissue
  • C57 mice use non-exposure intratracheal injection.
  • the normal group was injected with the same amount of normal saline through the trachea at one time, and the experimental group was injected with 5 ⁇ g of IFN- ⁇ , IFN- ⁇ , IFN- ⁇ +CH223191 or IFN- ⁇ model+CH223191 through the trachea.
  • the medicine is injected, immediately rotate the animal upright to make the medicine evenly distributed in the lungs.
  • the drug was administered once a day, and the lung function was measured and lung tissue samples were collected after four consecutive days of administration. Lung tissue collection: After the mouse is anesthetized with barbital sodium, the mouse is sacrificed, and the heart is perfused.
  • the lung tissue is taken out, and the blood stains on the lung tissue surface are cleaned with preparatory normal saline. Immediately after the above operation, the tissue was stored at -80°C. A part of the lung tissue was immediately stored in 4% paraformaldehyde for the preparation of immunohistochemical staining.
  • PBS PBS is given to the trachea every day
  • Experimental group 1 (IFN- ⁇ model +PBS): daily tracheal treatment with 5 ⁇ g/mouse IFN- ⁇ +PBS;
  • mice daily tracheal administration of 10 ⁇ g/mouse IFN- ⁇ +10mg/kg CH223191;
  • mice 10 ⁇ g/mouse IFN- ⁇ was given to the trachea every day.
  • Example 5 AHR inhibitor reverses interstitial pneumonia caused by SARS-CoV-2 infection
  • the human ACE2 transgenic C57 mice were divided into the following groups:
  • Control group intranasal injection of the same amount of normal saline as the treatment group;
  • Model group intranasal administration of 10 5 TCID 50 SARS-CoV-2 virus particles at a time;
  • Treatment group After intranasal administration of 10 5 TCID 50 SARS-CoV-2 virus particles, 10 mg/kg CH223191 was administered to the tail vein, once a day, for a total of 5 administrations.
  • mice Five days after the virus infection, the mice were anesthetized with sodium barbital, the lung tissue was taken out, and a part of the lung tissue was immediately placed in 4% paraformaldehyde for preservation for immunohistochemical analysis.
  • the AhR inhibitor of the anti-respiratory viral pneumonia preparation of the present application can effectively inhibit virus-induced pathological mucus produced by the respiratory system of the body, and it is expected to become a potential drug for the treatment of lung diseases caused by respiratory viral infections.
  • IFN- ⁇ and IFN- ⁇ are supposed to play an anti-viral effect, but they have other negative effects (that is, promote the production of more mucus in the lungs).
  • AhR inhibitors IDO works through the AhR pathway) reverse this negative effect.
  • the anti-respiratory viral pneumonia preparation of the present application can also enhance the systemic immune response, thereby killing the virus, and has the advantages of high safety and no toxic side effects.

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Abstract

La présente demande concerne l'utilisation d'un inhibiteur de petite molécule dans le traitement de la pneumonie virale respiratoire. En particulier, la présente demande se rapporte à une nouvelle utilisation d'un inhibiteur d'AhR dans le traitement ou l'amélioration d'une infection virale respiratoire. L'inhibiteur destiné à traiter une infection virale selon la présente demande peut inhiber efficacement la production de mucus pathologique par des tissus pulmonaires du corps induite par un virus, et l'inhibiteur d'AhR est censé devenir un médicament potentiel pour le traitement de maladies pulmonaires provoquées par une infection virale respiratoire.
PCT/CN2020/113478 2020-06-17 2020-09-04 Utilisation d'un inhibiteur de petites molécules dans le traitement de la pneumonie virale respiratoire Ceased WO2021253647A1 (fr)

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CN202010701456.6A CN111803635B (zh) 2020-06-17 2020-07-20 小分子抑制剂在治疗呼吸道病毒性肺炎上的应用
CN202010701456.6 2020-07-20

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