WO2017223178A1 - Traitement d'infections virales par des inhibiteurs d'impdh - Google Patents

Traitement d'infections virales par des inhibiteurs d'impdh Download PDF

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WO2017223178A1
WO2017223178A1 PCT/US2017/038500 US2017038500W WO2017223178A1 WO 2017223178 A1 WO2017223178 A1 WO 2017223178A1 US 2017038500 W US2017038500 W US 2017038500W WO 2017223178 A1 WO2017223178 A1 WO 2017223178A1
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phenyl
virus
ureido
methoxy
mammal
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PCT/US2017/038500
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Xiao Tong
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Trek Therapeutics, Pbc
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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
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • nucleotide synthesis in organisms is required for the cells in those organisms to divide and replicate. Nucleotide synthesis in mammals may be achieved through one of two pathways: the de novo synthesis pathway or the salvage pathway. Different cell types use these pathways to a different extent.
  • Inosine-5' -monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the de novo synthesis of guanine nucleotides.
  • IMPDH catalyzes the NAD-dependent oxidation of inosine-5 '-monophosphate (IMP) to xanthosine-5' -monophosphate (XMP) [Jackson R. C. et. al., Nature, 256, pp. 331- 333, (1975]).
  • IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y. Natsumeda & S. F. Carr, Ann. N. Y. Acad., 696, pp. 88-93 (1993)] .
  • the prokaryotic forms share 30- 40% sequence identity with the human enzyme.
  • IMPDH type I and type II form active tetramers in solution, with subunit molecular weights of 56 kDa [Y. Yamada et. al., Biochemistry, 27, pp. 2737-2745 (1988)] .
  • Nucleoside analogs such as tiazofurin, ribavirin (RBV), and mizoribine also inhibit IMPDH [L. Hedstrom, et. al. Biochemistry, 29, pp. 849-854 (1990)]. These compounds, however, suffer from lack of specificity to IMPDH.
  • IMPDH inhibitors of different classes have been described.
  • One such IMPDH inhibitor is the compound (S)-/V-3-[3-(3-methoxy-4- ox- azol-5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester, the structure (shown below) and properties of which are described in J. Jain et al., Pharmaceutical Sciences 90:625-637 (2000) and W. Markland et al.,
  • Another IMPDH inhibitor is the compound (i?)-l-cyanobutan-2-yl ((5)- l-(3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate, the structure and properties of which are described in U.S. Pat. Nos. 6,498,178 and 7,432,290.
  • This compound is referred to as VX-944 throughout this application and has the following structure.
  • Hemorrhagic fever viruses are viruses classified in several taxonomic families. HFVs cause a variety of disease syndromes with similar clinical characteristics, referred to as acute hemorrhagic fever syndromes. The pathophysiologic hallmarks of HFV infection are microvascular damage and increased vascular permeability.
  • HFVs that are RNA viruses include Arenaviridae such as Lassa, as well as South American hemorrhagic fevers including Junin, Machupo, Guanarito, and Sabia viruses, which are the causative agents of Lassa fever and Argentine, Venezuelan,
  • Hemorrhagic fever viruses are highly infectious by aerosol; are associated with high morbidity and, in some cases, high mortality; and are thought to pose a serious risk as biologic weapons.
  • HFVs pathogenesis of HFVs. All HFVs can produce thrombocytopenia, and some also cause platelet dysfunction. Infection with Ebola and Marburg viruses, Rift Valley fever virus, and yellow fever virus causes destruction of infected cells.
  • Disseminated intravascular coagulation is characteristic of infection with Filoviridae.
  • Ebola and Marburg viruses may cause a hemorrhagic diathesis and tissue necrosis through direct damage to vascular endothelial cells and platelets with impairment of the microcirculation, as well as cytopathic effects on parenchymal cells, with release of immunologic and inflammatory mediators.
  • Arenaviridae appear to mediate hemorrhage via the stimulation of inflammatory mediators by macro-phages, thrombocytopenia, and the inhibition of platelet aggregation.
  • the incubation period of HFVs ranges from 2 to 21 days. The clinical presentations of these diseases are nonspecific and variable, making diagnosis difficult. It is noteworthy that not all patients will develop hemorrhagic manifestations. Even a significant proportion of patients with Ebola virus infections may not demonstrate clinical signs of hemorrhage.
  • Initial symptoms of the acute HFV syndrome may include fever, headache, myalgia, rash, nausea, vomiting, diarrhea, abdominal pain, arthralgias, myalgias, and malaise.
  • Illness caused by Ebola, Marburg, Rift Valley fever virus, yellow fever virus, Omsk hemorrhagic fever virus, and Kyasanur Forest disease virus are characterized by an abrupt onset, whereas Lassa fever and the diseases caused by the Machupo, Junin, Guarinito, and Sabia viruses have a more insidious onset.
  • Initial signs may include fever, tachypnea, relative bradycardia, hypotension (which may progress to circulatory shock), conjunctival injection, pharyngitis, and lymphadenopathy.
  • Encephalitis may occur, with delirium, seizures, cerebellar signs, and coma.
  • Most HFVs cause cutaneous flushing or a macular skin rash, although the rash may be difficult to appreciate in dark- skinned persons and varies according to the causative virus.
  • Hemorrhagic symptoms when they occur, develop later in the course of illness and include petechiae, purpura, bleeding into mucous membranes and conjunctiva, hematuria, hematemesis, and melena. Hepatic involvement is common, and renal involvement is proportional to cardiovascular compromise.
  • Laboratory abnormalities include leukopenia (except in some cases of Lassa fever), anemia or hemoconcentration, and elevated liver enzymes; DIC with associated coagulation abnormalities and thrombocytopenia are common. Mortality ranges from less than 1% for Rift Valley fever to 70% to 90% for Ebola and Marburg virus infections
  • Clinical diagnostic criteria based on WHO surveillance standards for acute hemorrhagic fever syndrome include temperature greater than 101 F (38.3 C) of less than 3 weeks' duration; severe illness and no predisposing factors for hemorrhagic manifestations; and at least two of the following hemorrhagic symptoms: hemorrhagic or purple rash, epistaxis, hematemesis, hematuria, hemoptysis, blood in stools, or other hemorrhagic symptom with no established alternative diagnosis.
  • Laboratory techniques for the diagnosis of HFVs include antigen detection, IgM antibody detection, isolation in cell culture, visualization by electron microscopy, immunohistochemical techniques, and reverse transcriptase-polymerase chain reaction.
  • Chikungunya virus is an alpha virus that belongs to the family Togaviridae. CHIKV is transmitted to humans by mosquitoes. The reemergence of CHIKV in many parts of the world is a significant public health concern. Since the 2005-2006 chikungunya fever epidemic in the Indian Ocean island of La R'eunion, millions of people in more than 40 countries including India, Malaysia, Indonesia, Thailand, Singapore, the United States, and some European countries have been infected. Acute infection lasts for 1-10 days, symptoms include fever, headache, fatigue, nausea, vomiting, rash, myalgia, and severe arthralgia.
  • Polyarthralgia may persist in ⁇ 10% of cases for several months causing serious economic and social impacts.
  • Zika virus is a member of the Flavivirus genus of the
  • Flaviviridae family It is closely related to dengue virus, with approximately 43% amino acid identity across the viral polyprotein, which has posed challenges to accurate diagnosis of ZIKV infections.
  • ZIKV is transmitted to humans by mosquitoes. Since 2007, ZIKV spread throughout Oceania and then was detected in Brazil in early 2015, and within a year has reached Latin America and the Caribbean. Further spread of the virus is anticipated, and imported cases already have been reported in the United States and Europe. Historically, ZIKV infection caused a mostly self-limiting disease in humans ranging from no signs or symptoms to an influenza-like viral illness that appeared similar in the early stages to those caused by other epidemic arboviruses.
  • ZIKV Zika virus
  • Described herein is a method of treating or reducing the risk or severity of a hemorrhagic virus infection in a mammal that includes
  • an IMPDH inhibitor selected from (S)-/V-3-[3-(3-methoxy-4-ox- azol-5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester (VX-497) and (i?)-l-cyanobutan-2-yl ((S)-l-(3-(3-(3- methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate (VX-944).
  • an IMPDH inhibitor selected from (S)-/V-3-[3-(3-methoxy-4-ox- azol-5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester (VX-497) and (i?)-l-cyanobutan-2-yl ((S)-l-(3-(3-(
  • the hemorrhagic virus is lassa, junin, or ebola.
  • the method further includes administering ribavirin (e.g., a therapeutically effective amount of ribavirin to the mammal.
  • ribavirin e.g., a therapeutically effective amount of ribavirin
  • the method further includes administering T- 705 (e.g., a therapeutically effective amount of T-705) to the mammal.
  • T- 705 e.g., a therapeutically effective amount of T-705
  • the method further includes administering both T-705 and ribavirin to the mammal.
  • the method also includes administering both T-705 and ribavirin to the mammal.
  • Also described herein is a method of treating or reducing the risk or severity of a chikungunya virus infection in a mammal that includes
  • an IMPDH inhibitor selected from (S)-/V-3-[3-(3-methoxy-4-ox- azol-5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester (VX-497) and (i?)-l-cyanobutan-2-yl ((S)-l-(3-(3-(3- methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate (VX-944).
  • an IMPDH inhibitor selected from (S)-/V-3-[3-(3-methoxy-4-ox- azol-5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester (VX-497) and (i?)-l-cyanobutan-2-yl ((S)-l-(3-(3-(
  • the method further includes administering ribavirin (e.g., a therapeutically effective amount of ribavirin) to the mammal.
  • ribavirin e.g., a therapeutically effective amount of ribavirin
  • the method further includes administering T- 705 (e.g., a therapeutically effective amount of T-705) to the mammal.
  • T- 705 e.g., a therapeutically effective amount of T-705
  • the method further includes administering both T-705 and ribavirin to the mammal.
  • a mis ethod of treating or reducing the risk or severity of a zika virus infection in a mammal that includes administering a therapeutically effective amount of an IMPDH inhibitor selected from (S)-/V-3-[3- (3-methoxy-4-ox- azol-5-yl-phenyl)ureido]-benzylcarbamic acid
  • the method further includes administering ribavirin (e.g., a therapeutically effective amount of ribavirin) to the mammal.
  • ribavirin e.g., a therapeutically effective amount of ribavirin
  • the method further includes administering T- 705 (e.g., a therapeutically effective amount of T-705) to the mammal.
  • T- 705 e.g., a therapeutically effective amount of T-705
  • the method further includes administering both T-705 and ribavirin to the mammal.
  • compositions that includes: (a) a therapeutically effective amount of (S)-/V-3-[3-(3-methoxy-4-ox- azol-5-yl- phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester, (b) from about 60 mg to about 1200 mg of ribavirin, and (c) a pharmaceutically acceptable carrier.
  • the amount of (S)-/V-3-[3-(3-methoxy-4-ox- azol- 5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester is in the range of from about 150 mg to about 1500 mg.
  • compositions that includes: (a) a therapeutically effective amount of (i?)-l-cyanobutan-2-yl ((5)-l-(3-(3-(3- methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate, (b) from about 60 mg to about 1200 mg of ribavirin, and (c) a pharmaceutically acceptable carrier.
  • the amount of (i?)-l-cyanobutan-2-yl ((5)-l-(3- (3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate is in the range of from about 150 mg to about 1500 mg.
  • composition that includes: (a) a therapeutically effective amount of (S)-/V-3-[3-(3-methoxy-4-ox- azol-5-yl- p he nyl)ureido] -benzyl carbamic acid tetrahydrofuran-3-yl-ester, (b) from about 600 mg to about 2400 mg of T-705, and (c) a pharmaceutically acceptable carrier.
  • the amount of (S)-/V-3-[3-(3-methoxy-4-ox- azol- 5-yl-phenyl)ureido]-benzylcarbamic acid tetrahydrofuran-3-yl-ester is in the range of from about 150 mg to about 1500 mg.
  • compositions that includes: (a) a therapeutically effective amount of (i?)-l-cyanobutan-2-yl ((5)-l-(3-(3-(3- methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate, (b) from about 600 mg to about 2400 mg of T-705, and (c) a pharmaceutically acceptable carrier.
  • the amount of (i?)-l-cyanobutan-2-yl ((5)-l-(3- (3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)phenyl)ethyl)carbamate is in the range of from about 150 mg to about 1500 mg.
  • treatment of a viral infection includes reducing the viral load in a patient.
  • treatment of a viral infection includes reducing, e.g., reducing to an undetectable level, viral shedding into bodily fluids or reducing viral load in infected cells or organs.
  • Figure 1 shows the cytotoxicity of test compounds on Day 1.
  • Figure 2 shows the cytotoxicity of test compounds on Day 3.
  • Figure 3 shows the cytotoxicity of test compounds on Day 7.
  • Figure 4 shows the cytotoxicity of test compounds in the presence of 100 ⁇ guanosine on Day 7.
  • Figure 5 shows the activity of VX-497 against Ebola virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 6 shows the activity of VX-944 against Ebola virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 7 shows the activity of T-705 against Ebola virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 8 shows the activity of VX-497 against Lassa virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 9 shows the activity of VX-944 against Lassa virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 10 shows the activity of T-705 against Lassa virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 11 shows the activity of VX-497 against Junin virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 12 shows the activity of VX-944 against Junin virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 13 shows the activity of T-705 against Junin virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 14 shows the activity of VX-497 and VX-944 against Chikungunya virus in the absence and presence of 100 ⁇ guanosine.
  • Figure 15 shows the cytotoxicity of VX-497 and VX-944 in the absence and presence of 100 ⁇ guanosine.
  • Figure 16 shows the activity of combination treatment of VX-497 and ribavirin (RBV) against Junin virus.
  • Figure 17 shows the activity of combination treatment of VX-497 and ribavirin (RBV) against Lassa virus.
  • Figure 18 shows the activity of combination treatment of VX-497 and T-705 against Ebola virus.
  • Figure 19 shows the activity of combination treatment of VX-497 and ribavirin against Zika virus.
  • Figure 20 shows the activity of VX-944 against Zika virus.
  • Figure 21 shows the activity of ribavirin against Zika virus.
  • Figure 22 shows the cytotoxicity of VX-497 and the activity of VX- 497 against Zika virus.
  • Figure 23 shows the activity of combination treatment of VX-497 (3.3 ⁇ and 10 ⁇ ) with ribavirin (33 ⁇ and 100 ⁇ ) against Zika virus.
  • Described herein are methods for treating or reducing the risk of certain viral infections by administering VX-497, VX-944, or one of these agents in combination with one or more other antiviral agents to a subject in need of treatment.
  • the subject is mammalian, most preferably the subject is a human patient.
  • VX-497 or VX-944 is administered prophylactically to persons at high risk because of contact with suspected disease carriers, or in carriers who are asymptomatic.
  • the methods described herein are applicable to treating or reducing the risk or severity of hemorrhagic viral infections, including but not limited to Arenaviridae such as Lassa, as well as South American hemorrhagic fevers including Junin, Machupo, Guanarito, and Sabia viruses, which are the causative agents of Lassa fever and Argentine, Venezuelan, and Brazilian hemorrhagic fevers, respectively, Whitewater Arroyo virus and Flexal virus; Filoviridae (Ebola and Marburg viruses);
  • Bunyaviridae Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus, hemorrhagic fever with renal syndrome-associated hantaviruses, including Hantaan virus, Seoul virus, Dobrava virus (also referred to as Dobrava-Belgrade virus), and Puumala virus, and hantavirus pulmonary syndrome-associated hantaviruses, including Bayou virus, Black Creek Canal virus, New York virus, Sin Nombre virus, Andes virus, Oran virus, Juquitiba virus, Website Negra virus, and Lechiguanas virus; and Flaviviridae (dengue, dengue fever, dengue hemorrhagic fever, dengue shock syndrome, Kyasanur Forest disease, Omsk hemorrhagic fever, yellow fever).
  • the hemorrhagic viral infection is Lassa.
  • the viral infection is junin.
  • the viral infection is ebola.
  • VX-497 or VX-944 may be administered as dosages in the range of about 0.01-100 mg/kg. Dosages may be administered one or more times per week, preferably on a daily basis, with dosages administered one or more times per day. The dosages may be administered orally, by intravenous injection, by intramuscular injection, although other forms of injection, inhalation, and infusion may be utilized.
  • the pharmaceutical compositions described herein generally include a pharmaceutically acceptable carrier, with respect to standard pharmaceutical practice (such as described in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins).
  • VX-497 or VX-944 is administered at a dosage within a range of about 0.1-100 mg/kg, more preferably at a dosage of about 0.3-30 mg/kg.
  • Arenaviruses pose an ongoing public health concern both from naturally acquired infections and the potential for use as a biothreat agent.
  • the family Arenaviridae is comprised of enveloped viruses with an ambisense, bi-segmented genome. Its 22 members are divided into 2 serocomplexes.
  • the lymphocytic choriomeningitis-Lassa complex contains the five known "Old World” viruses while the Tacaribe complex is made up of 17 "New World” viruses of North and South America.
  • Each virus is associated with a single rodent species or with a couple of closely related rodent species reservoir (the possible exception is Tacaribe, which has only been isolated from two species of bats). This close association with the rodent host limits the geographic range of the virus to that of the reservoir.
  • LCMV being associated with the ubiquitous Mus musculus, is the only arenavirus found worldwide.
  • Asymptomatically infected rodents come into contact with humans, who become infected through the inhalation of virus in aerosolized excreta.
  • Most arenaviruses have not been associated with human infection and not all arenaviruses known to infect humans cause disease. However, several arenaviruses do cause disease in humans that ranges from mild to very severe. The most important are LCMV, which causes a rarely fatal CNS syndrome, Lassa virus, the etiological agent of Lassa fever, and Junin, Machupo, Guanarito, and Sabia, the causative agents of the South American hemorrhagic fevers.
  • Lassa fever like the Lassa virus reservoir, Mastomys sp., is endemic to West Africa. The disease is characterized by fever, weakness, malaise, headache and sore throat, with an onset 7-18 days after infection. Other common symptoms include joint and back pain, cough, vomiting, and diarrhea. Unlike the hemorrhagic fevers, there is no associated skin rash, ecchymoses, or petechiae. Case fatality among hospitalized patients is 15- 20%, but among all Lassa infections may be as low as 2-3%. Aerosolized person-to-person transmission has not been shown to occur. Contact with the secretions of an infected person is a significant risk factor, however.
  • Junin, Machupo, Guanarito, and Sabia viruses are the etiological agents of the South American hemorrhagic fevers: Argentine, Venezuelan, and Brazilian hemorrhagic fever, respectively. Though distinct, all have similar presentations that include fever, malaise, and myalgia beginning 1-2 weeks after infection. As disease worsens, additional symptoms develop: gastrointestinal distress, dizziness, headache, photophobia, retroorbital pain, tachycardia, petechiae, and conjunctival injection. Machupo infection appears to have the greatest propensity for person-to-person spread, with nosocomial and intrafamilial spread documented. Unlike the other hemorrhagic fever arenaviruses, but similar to Lassa fever infection, deafness has been observed following Guanarito virus infection. Case fatality rate for the South American hemorrhagic fever viruses is around 20%.
  • the nucleoside analogue Ribavirin (RBV) is the primary antiviral therapeutic for Lassa fever and is a promising therapy for arenavirus hemorrhagic fever.
  • ribavirin therapy may prevent or relieve acute hemorrhagic fever, its use in arenavirus infection has sometimes led to late neurologic disease.
  • Vero cells were seeded in 96-well plates for 24 hours before being dosed with serially diluted compounds. One plate for each compound was collected on Day 1, 3 and 7 and cytoxicity was measured using the CellTiter-Glo® Luminescent Cell Viability assay (Promega). In the guanosine reversal experiment, 100 ⁇ guanosine was added to growth media.
  • Vero cells were seeded in 12-well plates for 24 hours. Cells were infected with 0.1 MOI of viruses in 100 of media. After a 1 hour incubation, the media was removed and fresh media containing serially diluted compounds were added to the wells. Aliquots (100 ⁇ ,) were collected throughout Day 0 and Day 7. In the guanosine reversal experiment, 100 ⁇ guanosine was added to growth media. To determine viral titer by plaque assay, samples collected at various time-points were serialy diluted at a 1: 10 dilution and used to infect 6-well plates of Vero cells.
  • agarose overlay was added.
  • plates were fixed with 10% formaldehyde and stained with 0.25% crystal violet. The reduction in viral titer in the presence of test compounds was reported.
  • viral RNA was also purified from culture supernatants on Day 2, and compound inhibition of viral RNA was measured by qRT-PCR.
  • virus and cells were mixed in the presence of test compound and incubated for 3 days.
  • the virus was pretitered such that control wells exhibit 85 to 95% loss of cell viability due to virus replication. Therefore, antiviral effect or cytoprotection is observed when compounds prevent virus replication.
  • CPE viral cytopathic effects
  • Figures 1-3 show a slight increase in cytotoxicity of VX-497 and VX-944 from Day 1 to Day 7 during treatment.
  • the CC50 ( ⁇ ) on Day 7 was 9.5 for VX-497, and 2.2 for VX-944.
  • the two control compounds favipiravir (T-705) and RBV had CC50 > 50 ⁇ .
  • the highest concentration of VX-497 and VX-944 was 10 ⁇ and 2 ⁇ respectively, without exceeding their CC50 values.
  • Figure 4 shows that the cytotoxicity of VX-497 and VX-944 was reversed by the addition of guanosine, consistent with their MOA as IMPDH inhibitors.
  • Figures 5-7 demonstrate the inhibition of Ebola virus replication by VX-497, VX-944 and the control compound T-705. At the top
  • * -/+G is the absence or presence of guanosine
  • Figures 8-10 demonstrate the inhibition of Lassa virus replication by VX-497, VX-944 and the control compound RBV.
  • 10 ⁇ concentration reduction in virus titer ( ⁇ 1-1.6 log pfu/ml) by VX-497 was observed during the treatment period (see Table 2).
  • Addition of guanosine (100 ⁇ ) reversed the inhibition.
  • Inhibition by VX-944 was observed on Day 1 and Day 2, but diminished during later time points.
  • * -/+G is the absence or presence of guanosine
  • Figures 11-13 demonstrate the inhibition of Junin virus replication by VX-497, VX-944 and the control compound RBV. At the top concentration, maximum reduction in virus titer ( ⁇ 3 log pfu/ml) by VX-497 and VX-944 was observed around Day 3 (see Table 3). Addition of guanosine (100 ⁇ ) reversed the inhibition, consistent with their MOA as IMPDH inhibitors.
  • * -/+G is the absence or presence of guanosine
  • Figures 14-15 show the therapeutic window between antiviral activity and cytotoxicity for VX-497 and VX-944, with CC50/EC50 of 15 and 400 respectively. Addition of 100 ⁇ Guanosine reversed the inhibition, consistent with their MOA as IMPDH inhibitors.
  • Figure 16 shows the combination treatment of VX-497 (3.3 ⁇ and 10 ⁇ ) with RBV (33 ⁇ and 100 ⁇ ) against Junin virus. Inhibition of viral replication was enhanced under combination of VX-497 and RBV, compared with either single agent. On Day 3, when maximum inhibition was observed, virus titer reduction by combination treatment was numerically larger than the additive effect expected for the both single agents used together - notably, up to 5 log reduction in pfu/ml was achieved with 10 ⁇ and 100 ⁇ RBV (see Table 4).
  • Figure 17 shows the combination treatment of VX-497 (3.3 ⁇ and 10 ⁇ ) with RBV (33 ⁇ and 100 ⁇ ) against Lassa virus. Inhibition of viral replication was enhanced using a combination of VX-497 and RBV, compared with either single agent alone. On Day 3, when maximum inhibition was observed, virus titer reduction by combination treatment was numerically larger than the additive effect expected for the both single agents used together (see Table 5).
  • Figure 18 shows the combination treatment of VX-497 (3.3 ⁇ and 10 ⁇ ) with T-705 (33 ⁇ and 100 ⁇ ) against Ebola virus. Inhibition of viral replication was enhanced using a combination of VX-497 and T-705 compared with either single agent, but was numerically less than additive of single agents (see data from Day 5 in Table 6).
  • Figures 19-21 demonstrate the inhibition of Zika virus replication by VX-497, VX-944 and the control compound RBV. Reduction in virus titer ( ⁇ 2-3 log pfu/ml) by VX-497 and VX-944 was observed during the early treatment period at 10 and 2 ⁇ concentration respectively (see Table 7). Addition of guanosine (100 ⁇ ) reversed the inhibition. In a separate experiment, VX-497 inhibited Zika virus with an EC50 of 0.4 ⁇ by qRT-PCR assay and a CC50 of 7.2 ⁇ in Huh7 cells ( Figure 22).
  • Figure 23 shows the combination treatment of VX-497 (3.3 ⁇ and 10 ⁇ ) with ribavirin (33 ⁇ and 100 ⁇ ) against Zika virus. Inhibition of viral replication was enhanced at Day 3 using a combination of VX-497 and ribavirin compared with either single agent (see data from Day 2 in Table 8).
  • VX-497 and VX- 944 exhibit broad spectrum antiviral activities, and that combination of VX- 497 with other antivirals such as T-705 or RBV enhance virus inhibition over single agents, and that the level of enhancement varies, with less enhancement seen with VX-497 plus T-705 against Ebola and greater enhancement seen with VX-497 plus RBV against Junin virus.

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Abstract

L'invention concerne des méthodes de traitement ou de réduction du risque ou de la gravité d'une infection par un virus hémorragique ou de certaines autres infections virales chez un mammifère, qui consistent à administrer une quantité thérapeutiquement efficace d'un inhibiteur d'IMPDH choisi parmi le tétrahydrofuran-3-yl-ester de l'acide (S)-N-3-[3-(3-méthoxy-4-ox-azol-5-yl-phényl)uréido]-benzylcarbamique (VX-497) et le (R)-1-cyanobutan-2-yl ((S)-1-(3-(3-(3-méthoxy-4-(oxazol-5-yl)phényl)uréido)phényl)éthyl)carbamate (VX-944) éventuellement en association avec un autre médicament antiviral.
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WO2021007283A1 (fr) * 2019-07-09 2021-01-14 Regents Of The University Of Minnesota Potentialisation de nucléobases antivirales en tant que thérapie par virus à arn
US20220096468A1 (en) * 2018-12-25 2022-03-31 Fujifilm Toyama Chemical Co., Ltd. Therapeutic agent for RNA viral infection comprising a combination of pyrazine derivative and compound which increases amount of pyrazine derivative ribose triphosphate in cell

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