WO2022058323A1 - Composés pour le traitement d'infections virales - Google Patents

Composés pour le traitement d'infections virales Download PDF

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Publication number
WO2022058323A1
WO2022058323A1 PCT/EP2021/075269 EP2021075269W WO2022058323A1 WO 2022058323 A1 WO2022058323 A1 WO 2022058323A1 EP 2021075269 W EP2021075269 W EP 2021075269W WO 2022058323 A1 WO2022058323 A1 WO 2022058323A1
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dna
inhibitor
subject
infection
sars
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PCT/EP2021/075269
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English (en)
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Ulrich Betz
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Merck Patent Gmbh
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/215—IFN-beta
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • the present invention provides for the use of inhibitors of DNA-dependent protein kinase (DNA-PK) in the treatment of coronavirus infections, including SARS-CoV infections such as COVID-19.
  • DNA-PK DNA-dependent protein kinase
  • DDR DNA damage response
  • HR homologous recombination-guided repair
  • NHEJ non-homologous end joining
  • DNA-dependent protein kinase is a serine/threonine kinase and a key driver of NHEJ repair. It is known that there is a complex network of interactions between the DDR systems and the life cycle of viruses, and that the cellular DDR can either promote or restrict virus growth by directly manipulating viral nucleic acids and by activating signaling pathways that can significantly impact viral life cycles. There appears to be a mixture or positive and negative regulation of virus infection by NHEJ machinery.
  • Coronaviruses are positive-sense, single-stranded RNA (ssRNA) viruses of the order Nidovirales, in the family Coronaviridae. There are four sub-types of coronaviruses - alpha, beta, gamma and delta - with the Alphacoronaviruses and Betacoronaviruses infecting mostly mammals, including humans.
  • ssRNA single-stranded RNA
  • SARS-CoV-1 severe acute respiratory syndrome
  • MERS-CoV Middle East respiratory syndrome
  • SARS-CoV-2 COVID-19
  • SARS-CoV-2 closely resembles SARS-CoV-1 , the causative agent of SARS epidemic of 2002-03 (Fung, et al, Annu. Rev. Microbiol. 2019. 73:529-57). Severe disease has been reported in approximately 15% of patients infected with SARS-CoV-2, of which one third progress to critical disease (e.g. respiratory failure, shock, or multiorgan dysfunction (Siddiqi, et al, J. Heart and Lung Trans. (2020), doi: https://doi.org/10.1016/j-healun.2020.03.012, Zhou, et al, Lancet 2020; 395: 1054-62.
  • critical disease e.g. respiratory failure, shock, or multiorgan dysfunction
  • the virus has a high transmission rate, likely linked to high early viral loads and lack of pre-existing immunity (He, et. al, Nat Med 2020 https://doi.org/10.1038/s41591 -020-0869-5). It causes severe disease especially in the elderly and in individuals with comorbidities.
  • the global burden of COVID-19 is immense, and therapeutic approaches are increasingly necessary to tackle the disease.
  • Intuitive anti-viral approaches including those developed for enveloped RNA viruses like HIV-1 (lopinavir plus ritonavir) and Ebola virus (remdesivir) have been implemented in testing as investigational drugs (Grein et al, NEJM 2020 https://doi.org/10.1056/NEJMoa2007016j Cao, et al, NEJM 2020 DOI: 10.1056/NEJMoa2001282). But given that many patients with severe disease present with immunopathology, host-directed immunomodulatory approaches are also being considered, either in a staged approach or concomitantly with antivirals (Metha, et al, The Lancet 2020;
  • Figure 1 shows a flow diagram illustrating the different steps taken in the testing of antiviral activity of the DNA-PK inhibitor compound.
  • Figure 2 shows, for comparative purposes, viability of uninfected cells and those treated with 10 pM remdisivir as a control.
  • Figure 3 shows the viability of cells treated with 20 pM peposertib (“NCE-13”) under the same conditions as those of Figure 2.
  • Figure 4 shows the Propidium Iodide signal (total red object integrated intensity) of infected cells, uninfected cells, cells treated with 1 or 10 pM remdivisir and 20 pM peposertib (“NCE-13”).
  • the invention provides a DNA-PK inhibitor of the invention for use in the treatment of viral infections in a subject in need thereof.
  • the viral infection is a single-strand RNA viral infection.
  • the viral infection is a coronavirus infection.
  • the viral infection is a SARS-CoV1 , MERS-CoV, or SARS-CoV-2 infection.
  • the viral infection is a SARS-CoV-2 infection.
  • a second embodiment is a method of treating a coronavirus infection in a subject in need thereof, comprising administering an effective amount of a DNA-PK inhibitor, or a pharmaceutically acceptable salt thereof, to the subject.
  • the administration of the DNA-PK inhibitor reduces the viral load in the subject.
  • the DNA-PK inhibitor is administered prior to COVID-19 pneumonia development.
  • the DNA-PK inhibitor is administered prior to the subject developing a severe cytokine storm.
  • the subject has a mild to moderate SARS-CoV-2 infection.
  • the subject is asymptomatic at the start of the administration regimen.
  • Coronaviruses comprise a diverse group of enveloped positive-strand RNA viruses that are responsible for several human diseases, most notably the severe acute respiratory syndrome (SARS) which emerged in 2003. Perturbation of the host cell cycle regulation is a characteristic feature of infections by many DNA and RNA-viruses, including Corona-virus infectious bronchitis virus (IBV) (Xu L.H. et al.: Coronavirus Infection Induces DNA Replication Stress Partly through Interaction of Its Nonstructural Protein 13 with the p125 Subunit of DNA Polymerase; J Biol Chem. Nov 11 ; 286(45): 39546-39559.).
  • IBV Corona-virus infectious bronchitis virus
  • IBV infection was shown to induce cell cycle arrest at both S and G2/M phases for the enhancement of viral replication and progeny production.
  • Xu et al. have shown that activation of the cellular DNA damage response is one of the key mechanisms exploited by Coronavirus to induce cell cycle arrest.
  • the DNA damage response is mediated by members of the PIKK (phosphatidylinositol-3-kinase-like protein kinase) family of serine/threonine kinases including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3 related), and DNA-PK (DNA-dependent protein kinase).
  • PIKK phosphatidylinositol-3-kinase-like protein kinase family of serine/threonine kinases
  • ATM ataxia telangiectasia mutated
  • ATR ataxia telangiectasia and Rad3 related
  • DNA-PK DNA-dependent protein kinase
  • Xu et al showed that ATR-signaling was activated in IBV-infected H1299 as well as Vero cells. Suppression of the ATR kinase activity by chemical inhibitors and siRNA-mediated knockdown of ATR reduced IBV-induced ATR signaling and inhibited the replication of IBV. On the contrary, ATM pathway activation was not observed and DNA-PK inhibitors did not reduce IBV replication.
  • “mild to moderate” COVID-19 occurs when the subject presents as asymptomatic or with less severe clinical symptoms (e.g., low grade or no fever ( ⁇ 39.10), cough, mild to moderate discomfort) with no evidence of pneumonia, and generally does not require medical attention.
  • “moderate to severe” infection generally patients present with more severe clinical symptoms (e.g., fever >39.10, shortness of breath, persistent cough, pneumonia, etc.).
  • “moderate to severe” infection typically requires medical intervention, including hospitalization. During the progression of disease, a subject can transition from “mild to moderate” to “moderate to severe” and back again in one course of bout of infection.
  • Treatment of COVID-19 using the methods of this invention include administration of an effective amount of a DNA-PK inhibitor of the invention at any stage of the infection to prevent or reduce the symptoms associated therewith.
  • subjects will be administered an effective amount of a DNA-PK inhibitor of the invention after definitive diagnosis and presentation with symptoms consistent with a SARS-CoV2 infection, and administration will reduce the severity of the infection and/or prevent progression of the infection to a more severe state.
  • the clinical benefits upon such administration are described in more detail in the sections below.
  • One embodiment is use of a compound according to the following formula: or pharmaceutically acceptable salt thereof for treating a coronavirus infection in a subject in need thereof, as well as a method of treating a coronavirus infection in a subject in need thereof, comprising administering an effective amount of a DNA-PK inhibitor, or a pharmaceutically acceptable salt thereof to the subject.
  • the compound according to the above formula may also be designated as (S)-[2- Chloro-4-fluoro-5-(7-morpholin-4-yl-quinazolin-4-yl)-phenyl]-(6-methoxy-pyridazin-3-yl)- methanol, and is also known as peposertib (INN). Its preparation and properties are described in WO 2014/183850.
  • the above compound may either be used in its free form or as a pharmaceutically acceptable salt.
  • the free compound may be converted into the associated acid-addition salt by reaction with an acid, for example by reaction of equivalent amounts of the compound and the acid in an inert solvent, such as, for example, ethanol, and subsequent evaporation.
  • An exemplary embodiment of a pharmaceutically acceptable salt of the above compound is the fumarate salt.
  • salts of other organic or inorganic acids may be used.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • the group comprises one or more deuterium atoms.
  • the term “patient” or “subject”, as used herein, means an animal, preferably a human. However, “subject” can include companion animals such as dogs and cats.
  • the subject is an adult human patient.
  • the subject is a pediatric patient.
  • Pediatric patients include any human which is under the age of 18 at the start of treatment.
  • Adult patients include any human which is age 18 and above at the start of treatment.
  • the subject is a member of a high-risk group, such as being over 65 years of age, immunocompromised humans of any age, humans with chronic lung conditions (such as, asthma, COPD, cystic fibrosis, etc.), and humans with other co-morbidities.
  • the other co-morbidity is obesity, diabetes, and/or hypertension.
  • compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the compositions are administered orally.
  • the oral formulation of a compound of the invention is a tablet or capsule form.
  • the oral formulation is a solution or suspension which may be given to a subject in need thereof via mouth or nasogastric tube. Any oral formulations of the invention may be administered with or without food.
  • pharmaceutically acceptable compositions of this invention are administered without food.
  • pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of this invention are orally administered in any orally acceptable dosage form.
  • exemplary oral dosage forms are capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents are optionally also added.
  • Suitable pharmaceutically acceptable compositions of peposertib are described in WO 2018/178134, for instance.
  • compositions in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.
  • the total amount of DNA-PK inhibitor administered to the subject in need thereof is between about 5 mg to about 1000 mg per day.
  • the DNA-PK inhibitor is administered in a total amount of 5 mg to 1 g per day, for instance between 10 and 1000 mg per day, such as between 50 and 800 mg per day or between 100 and 400 mg per day.
  • the DNA-PK inhibitor is administered once a day. In another aspect of this embodiment, the DNA-PK inhibitor is administered twice a day.
  • the DNA-PK inhibitor is administered for a period of about 7 days to about 28 days. In one aspect of any of the above embodiments, the DNA-PK inhibitor is administered for about 14 days.
  • the subject is suffering from COVID-19 pneumonia. In one embodiment of this invention, the subject is suffering from one or more symptoms selected from chest congestion, cough, blood oxygen saturation (SpO2) levels below 94%, shortness of breath, difficulty breathing, fever, chills, repeated shaking with chills, muscle pain and/or weakness, headache, sore throat and/or new loss of taste or smell.
  • SpO2 blood oxygen saturation
  • the subject is suffering from a hyperinflammatory host immune response to a SARS-CoV-2 infection.
  • the hyperinflammatory host immune response is associated with one or more clinical indications selected from 1 ) reduced levels of lymphocytes, especially natural killer (NK) cells in peripheral blood; 2) high levels of inflammatory parameters (eg, C reactive protein [CRP], ferritin, d-dimer), and pro- inflammatory cytokines (eg, IL-6, TNF-alpha, IL-8, and/or IL-1 beta; 3) a deteriorating immune system demonstrated by lymphocytopenia and/or atrophy of the spleen and lymph nodes, along with reduced lymphocytes in lymphoid organs; 4) dysfunction of the lung physiology represented by lung lesions infiltrated with monocytes, macrophages, and/or neutrophils, but minimal lymphocytes infiltration resulting in decreased oxygenation of the blood; 5) acute respiratory distress syndrome (ARDS); 6) vasculitis;
  • the subject with COVID-19 is a pediatric patient suffering from vasculitis, including Kawasaki disease (i.e., Kawasaki syndrome) and Kawasaki-like disease.
  • Kawasaki disease i.e., Kawasaki syndrome
  • Kawasaki-like disease i.e., Kawasaki-like disease.
  • the subject is being treated inpatient in a hospital setting. In another embodiment, the subject is being treated in an outpatient setting. In one aspect of the preceding embodiments, the subject may continue administration of the DNA-PK inhibitor after being transitioned from being treated from an inpatient hospital setting to an outpatient setting.
  • the administration of the DNA-PK inhibitor results in one or more clinical benefit.
  • the one or more clinical benefit is selected from the group comprising: reduction of duration of a hospital stay, reduction of the duration of time in the Intensive Care Unit (ICU), reduction in the likelihood of the subject being admitted to an ICU, reduction in the rate of mortality, reduction in the likelihood of kidney failure requiring dialysis, reduction in the likelihood of being put on non-invasive or invasive mechanical ventilation, reduction of the time to recovery, reduction in the likelihood supplemental oxygen will be needed, improvement or normalization in the peripheral capillary oxygen saturation (SpO2 levels) without mechanical intervention, reduction of severity of the pneumonia as determined by chest imaging (eg, CT or chest X ray), reduction in the cytokine production, reduction of the severity of acute respiratory distress syndrome (ARDS), reduction in the likelihood of developing ARDS, clinical resolution of the COVID-19 pneumonia, and improvement of the PaOs/FiOz ratio.
  • the one or more clinical benefits includes the improvement or normalization in the peripheral capillary oxygen saturation (SpO2 levels) in the subject without mechanical ventilation or extracorporeal membrane oxygenation.
  • SpO2 levels peripheral capillary oxygen saturation
  • the one or more clinical benefits is reduction in the likelihood of being hospitalized, reduction in the likelihood of ICU admission, reduction in the likelihood being intubated (invasive mechanical ventilation), reduction in the likelihood supplemental oxygen will be needed, reduction in the length of hospital stay, reduction in the likelihood of mortality, and/or a reduction in likelihood of relapse, including the likelihood of rehospitalization.
  • the invention also provides a method of treating a viral infection in a subject in need thereof comprising administering an effective amount of a compound of the invention to the subject.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control subjects.
  • One embodiment of the invention is a method of treating a coronavirus infection in a subject in need thereof, comprising administering an effective amount of an DNA-PK inhibitor, or a pharmaceutically acceptable salt thereof, to the subject.
  • the subject is infected with SARS-CoV-2.
  • the administration of the DNA-PK inhibitor results in the reduction of the viral load in the subject.
  • the DNA-PK inhibitor is administered prior to COVID-19 pneumonia developing.
  • the subject has a mild to moderate SARS-CoV- 2 infection.
  • the subject is asymptomatic at the start of the administration regimen.
  • the subject has had known contact with a patient who has been diagnosed with a SARS-CoV-2 infection.
  • the subject begins administration of the DNA-PK inhibitor prior to being formally diagnosed with COVID-19.
  • One embodiment is a method of treating a subject with COVID-19 comprising administration of an effective amount of a DNA-PK inhibitor to the subject.
  • the subject has been previously vaccinated with a SARS-CoV-2 vaccine and develops vaccine-related exacerbation of infection, for example, an antibody-dependent enhancement or related antibody-mediated mechanisms of vaccine/antibody-related exacerbation.
  • the administration of the DNA-PK inhibitor results in one or more clinical benefits to the subject.
  • the one or more clinical benefits is shortening the duration of infection, reduction of the likelihood of hospitalization, reduction in the likelihood of mortality, reduction in the likelihood of ICll admission, reduction in the likelihood being placed on mechanical ventilation, reduction in the likelihood supplemental oxygen will be needed, and/or reduction in the length of hospital stay.
  • the one or more clinical benefits is avoidance of a significant proinflammatory response.
  • the one or more clinical benefit is the failure of the subject to develop significant symptoms of COVID-19.
  • the compounds of the invention can be administered before or following an onset of SARS-CoV-2 infection, or after acute infection has been diagnosed in a subject.
  • the aforementioned compounds and medical products of the inventive use are particularly used for the therapeutic treatment.
  • a therapeutically relevant effect relieves to some extent one or more symptoms of a disorder, or returns to normality, either partially or completely, one or more physiological or biochemical parameters associated with or causative of a disease or pathological condition.
  • Monitoring is considered as a kind of treatment provided that the compounds are administered in distinct intervals, e.g. in order to boost the response and eradicate the pathogens and/or symptoms of the disease.
  • the methods of the invention can also be used to reduce the likelihood of developing a disorder or even prevent the initiation of disorders associated with COVID-19 in advance of the manifestation of mild to moderate disease, or to treat the arising and continuing symptoms of an acute infection.
  • Treatment of mild to moderate COVID-19 is typically done in an outpatient setting.
  • Treatment of moderate to severe COVID-19 is typically done inpatient in a hospital setting. Additionally, treatment can continue in an outpatient setting after a subject has been discharged from the hospital.
  • the invention furthermore relates to a medicament comprising at least one compound according to the invention or a pharmaceutically acceptable salt thereof.
  • a “medicament” in the meaning of the invention is any agent in the field of medicine, which comprises one or more compounds of the invention or preparations thereof (e.g. a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow-up or aftercare of patients who suffer from clinical symptoms and/or known exposure to COVID-19.
  • the active ingredient may be administered alone or in combination with one or more additional therapeutic agents.
  • a synergistic or augmented effect may be achieved by using more than one compound in the pharmaceutical composition.
  • the active ingredients can be used either simultaneously or sequentially.
  • the DNA-PK inhibitor is administered in combination with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents is selected from anti-inflammatories, antibiotics, anti-coagulants, antiparasitic agent, antiplatelet agents and dual antiplatelet therapy, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-blockers, statins and other combination cholesterol lowering agents, specific cytokine inhibitors, complement inhibitors, anti-VEGF treatments, JAK inhibitors, immunomodulators, anti-inflammasome therapies, sphingosine-1 phosphate receptors binders, N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonists, corticosteroids, Granulocyte-macrophage colony-stimulating factor (GM-CSF), anti- GM-CSF, interferons, angiotensin receptor-neprilysin inhibitors, calcium channel blockers, vasodil
  • ACE angiotensin converting enzyme
  • the DNA-PK inhibitor is administered in combination with an antiviral agent.
  • the antiviral agent is remdesivir.
  • the antiviral agent is lopinavir-ritonavir, alone or in combination with ribavirin and interferon-beta.
  • the DNA-PK inhibitor is administrated in combination with a broadspectrum antibiotic.
  • the DNA-PK inhibitor is administered in combination with chloroquine or hydroxychloroquine. In one aspect of this embodiment, the DNA-PK inhibitor is further combined with azithromycin.
  • the DNA-PK inhibitor is administered in combination with interferon-1 -beta (Rebif®).
  • the DNA-PK inhibitor is administered in combination with one or more additional therapeutic agents selected from hydroxychloroquine, chloroquine, ivermectin, tranexamic acid, nafamostat, virazole, ribavirin, lopinavir/ritonavir, favipiravir, arbidol, leronlimab, interferon beta-1 a, interferon beta-1 b, beta-interferon, azithromycin, nitrazoxamide, lovastatin, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emapalumab, pirfenidone, belimumab,
  • the DNA-PK inhibitor is administered in combination with one or more anti-inflammatory agent.
  • the anti-inflammatory agent is selected from corticosteroids, steroids, COX-2 inhibitors, and non-steroidal anti-inflammatory drugs (NSAID).
  • the anti-inflammatory agent is diclofenac, etodolac, fenoprofen, flurbirprofen, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, prednisone, hydrocortisone, fludocortisone, bethamethasone, prednisolone, triamcinolone, methylprednisone, dexamethasone, fluticasone, and budesonide (alone or in combination with formoterol, salmeterol, or vilanterol).
  • the DNA-PK inhibitor is administered in combination with one or more immune modulators.
  • the immune modulator is a calcineurin inhibitor, antimetabolite, or alkylating agent.
  • the immune modulator is selected from azathioprine, mycophenolate mofetil, methotrexate, dapson, cyclosporine, cyclophosphamide, and the like.
  • the DNA-PK inhibitor is administered in combination with one or more antibiotics.
  • the antibiotic is a broad-spectrum antibiotic.
  • the antibiotic is a penicillin, anti-straphylococcal penicillin, cephalosporin, aminopenicillin (commonly administered with a betalactamase inhibitor), monobactam, quinoline, aminoglycoside, lincosamide, macrolide, tetracycline, glycopeptide, antimetabolite or nitroimidazole.
  • the antibiotic is selected from penicillin G, oxacillin, amoxicillin, cefazolin, cephalexin, cephotetan, cefoxitin, ceftriazone, augmentin, amoxicillin, ampicillin (plus sulbactam), piperacillin (plus tazobactam), ertapenem, ciprofloxacin, imipenem, meropenem, levofloxacin, moxifloxacin, amikacin, clindamycin, azithromycin, doxycycline, vancomycin, Bactrim, and metronidazole.
  • the DNA-PK inhibitor is administered in combination with one or more anti-coagulants.
  • the anti-coagulant is selected from apixaban, dabigatran, edoxaban, heparin, rivaroxaban, and warfarin.
  • the DNA-PK inhibitor is administered in combination with one or more antiplatelet agents and/or dual antiplatelet therapy.
  • the antiplatelet agent and/or dual antiplatelet therapy is selected from aspirin, clopidogrel, dipyridamole, prasugrel, and ticagrelor.
  • the DNA-PK inhibitor is administered in combination with one or more ACE inhibitors.
  • the ACE inhibitor is selected from benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.
  • the DNA-PK inhibitor is administered in combination with one or more angiotensin II receptor blockers.
  • the angiotensin II receptor blocker is selected from azilsartan, candesartan, eprosartan, irbesartan, losartan, Olmesartan, telmisartan, and valsartan.
  • the DNA-PK inhibitor is administered in combination with one or more beta-blockers.
  • the beta-blocker is selected from acebutolol, atenolol, betaxolol, bisoprolol/hydrochlorothiazide, bisoprolol, metoprolol, nadolol, propranolol, and sotalol.
  • the DNA-PK inhibitor is administered in combination with one or more alpha and beta-blocker.
  • the alpha and beta-blocker is carvedilol or labetalol hydrochloride.
  • the DNA-PK inhibitor is administered in combination with one or more interferons.
  • the DNA-PK inhibitor is administered in combination with one or more angiotensin receptor-neprilysin inhibitors.
  • the angiotensin receptor-neprilysin inhibitor is sacubitril/valsartan.
  • the DNA-PK inhibitor is administered in combination with one or more calcium channel blockers.
  • the calcium channel blocker is selected from amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisoldipine, and verapamil.
  • the DNA-PK inhibitor is administered in combination with one or more vasodilators.
  • the one or more vasodilator is selected from isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, and minoxidil.
  • the DNA-PK inhibitor is administered in combination with one or more diuretics.
  • the one or more diuretics is selected from acetazolamide, amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone, spironolactone, and torsemide.
  • the DNA-PK inhibitor is administered in combination with one or more muscle relaxants.
  • the muscle relaxant is an antispasmodic or antispastic.
  • the one or more muscle relaxants is selected from carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, tizanidine, baclofen, dantrolene, and diazepam.
  • the DNA-PK inhibitor is administered in combination with one or more antiviral medications.
  • the antiviral medication is remdesivir.
  • the DNA-PK inhibitor is administered in combination with one or more additional therapeutic agents selected from antiparasitic drugs (including, but not limited to, hydroxychloroquine, chloroquine, ivermectin), antivirals (including, but not limited to, tranexamic acid, nafamostat, virazole [ribavirin], lopinavir/ritonavir, favipiravir, leronlimab, interferon beta-1 a, interferon beta-1 b, beta-interferon), antibiotics with intracellular activities (including, but not limited to azithromycin, nitrazoxamide), statins and other combination cholesterol lowering and antiinflammatory drugs (including, but not limited to, lovastatin), specific cytokine inhibitors (including, but not limited to, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab
  • the combination of an DNA-PK inhibitor with one or more additional therapeutic agents reduces the effective amount (including, but not limited to, dosage volume, dosage concentration, and/or total drug dose administered) of the DNA-PK inhibitor and/or the one or more additional therapeutic agents administered to achieve the same result as compared to the effective amount administered when the DNA-PK inhibitor or the additional therapeutic agent is administered alone.
  • the combination of an DNA-PK inhibitor with the additional therapeutic agent reduces the total duration of treatment compared to administration of the additional therapeutic agent alone.
  • the combination of an DNA-PK inhibitor with the additional therapeutic agent reduces the side effects associated with administration of the additional therapeutic agent alone.
  • the combination of an effective amount of the DNA-PK inhibitor with the additional therapeutic agent is more efficacious compared to an effective amount of the DNA-PK inhibitor or the additional therapeutic agent alone. In one embodiment, the combination of an effective amount of the DNA- PK inhibitor with the one or more additional therapeutic agent results in one or more additional clinical benefits than administration of either agent alone.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a viral infection, or one or more symptoms thereof, as described herein.
  • treatment is administered after one or more symptoms have developed.
  • treatment is administered in the absence of symptoms.
  • treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a known exposure to an infected person and/or in light of comorbidities which are predictors for severe disease, or other susceptibility factors).
  • DNA- PK inhibitor peposertib (referred to as “NCE-13” in the Figures) was tested for antiviral effect using Vero E6 cells.
  • Vero E6 ATCC CRL-1586 cells were maintained in DMEM medium supplemented with 10% fetal calf serum (FCS), 2 mM L-glutamine, 100 ILI/mL penicillin and 100 pg/mL streptomycin. All incubations of cells and virus were at 37 G in a 5% CO2 atmosphere.
  • FCS fetal calf serum
  • Vero E6 cells were tested by seeding Vero E6 cells at a density of 7 x 10 3 cells in 384 - well plates one day before infection. On the day of infection, propidium iodide (1 pg/mL) was added to the cell monolayer followed by addition of peposertib at 20 pM. Vero E6 cell monolayer was infected 1 h after addition of compounds by SARS-CoV-2 with an MOI (multiplicity of infection) of 0.01 in 50 pL and incubated at 37 G for 72 h. The total infection volume per well was 50 pL.
  • MOI multiplicity of infection
  • Viability of cells was determined after 72 h of infection by using the CellTiter-Glo Luminescent Cell Viability Assay (Promega Inc.).
  • CellTiter-Glo reagents were prepared according to manufacturer protocol. The reaction was initiated by addition of 50 pL/well of the CellTiter-Glo reagent to cells. Assay plates were incubated for 10 min in the dark at RT prior to measurement. Luminescence was detected on the Synergy HTX Multi-Mode plate reader (Biotek). Data analysis was performed using Graphpad Prism 8.

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Abstract

La présente invention concerne un inhibiteur d'ADN-PK destiné à être utilisé dans le traitement d'infections à coronavirus, comprenant la COVID-19, seul ou en combinaison avec un ou plusieurs agents thérapeutiques supplémentaires.
PCT/EP2021/075269 2020-09-18 2021-09-15 Composés pour le traitement d'infections virales WO2022058323A1 (fr)

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