WO2022005871A1 - Méthodes de traitement d'une infection par le sars-cov-2 à l'aide d'inhibiteurs de la lipogenèse - Google Patents

Méthodes de traitement d'une infection par le sars-cov-2 à l'aide d'inhibiteurs de la lipogenèse Download PDF

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WO2022005871A1
WO2022005871A1 PCT/US2021/038908 US2021038908W WO2022005871A1 WO 2022005871 A1 WO2022005871 A1 WO 2022005871A1 US 2021038908 W US2021038908 W US 2021038908W WO 2022005871 A1 WO2022005871 A1 WO 2022005871A1
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inhibitor
optionally substituted
pharmaceutical composition
lipogenesis
acid
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PCT/US2021/038908
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Anders Michael NAAR
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy

Definitions

  • pandemic caused by SARS-CoV-2 infections (Coronaviral Disease 2019 (Covid-19)) caused about 9 million infections and about 460,000 deaths worldwide.
  • the pandemic is expected to expand in the late 2020, particularly, because of the lack of a therapeutically effective treatment for the disease. Therefore, methods of treating SARS-CoV-2 infection are desired.
  • the present disclosure provides methods of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of lipogenesis.
  • the inhibitor of lipogenesis can be an inhibitor of a lipogenic enzyme, such as an inhibitor of acetyl-CoA carboxylase 1 (ACC1), acetyl-CoA carboxylase 2 (ACC2), fatty acid synthase (FASN), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), stearoyl-CoA desaturase-1 (SCDl), Diacylglycerol O-Acyltransferase 1 (DGAT1), or Acetyl-CoA synthetase 2 (ACSS2).
  • An inhibitor of lipogenesis can be an activator of 5’ AMP-activated protein kinase (AMPK).
  • An inhibitor of lipogenic enzyme can be administered alone or in combination with an inhibitor of RNA-dependent RNA-polymerase (RdRp).
  • RdRp RNA-dependent RNA-polymerase
  • An inhibitor of lipogenic enzyme and/or an RdRp inhibitor can be administered in further combination with an anti-inflammatory compound, such as a steroidal or a non-steroidal anti inflammatory compound.
  • FIG.1 shows the effects of certain exemplary inhibitors of lipogenic enzymes on the cytopathic effect (CPE) of SARS-CoV-2 in cultured VERO-E6 cells.
  • FIG.2 shows the effects of certain exemplary inhibitors of lipogenic enzymes on the cytopathic effect (CPE) of SARS-CoV-2 in cultured Calu3 cells.
  • FIG.3 depicts the results of a combination of TOFA and Remdesivir on SARS-CoV-2-induced cytopathic effect (CPE) in Vero cells.
  • FIG.4 depicts the effect of TOFA on SARS-CoV-2 in various cell lines.
  • FIG.5A-5D depict the effect of TOFA on nucleocapsid expression (FIG.5A and FIG.5C) and spike glycoprotein expression (FIG.5B and FIG.5D).
  • FIG.6A-6C depict RNA-seq analysis of SARS-CoV-2-infected Huh-7 cells treated with TOFA.
  • FIG.7 depicts in vivo effect of TOFA administration on SARS-CoV-2 titer.
  • co-administration encompass administering two or more compounds to a subject so that both compounds and/or their metabolites are present in the subject at the same time.
  • Coadministration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both compounds are present.
  • Co-administered compounds may be in the same formulation.
  • Co- administered compounds may also be in different formulations.
  • inhibitor refers to a compound having the ability to inhibit a biological function of a target protein or a target biological process.
  • an inhibitor can inhibit the activity or expression of the target protein.
  • activator refers to a compound having the ability to activate or stimulate a biological function of a target protein or a target biological process. When activating a target protein, an activator can increase the activity or expression of the target protein.
  • a “sub-therapeutic amount” of a compound is an amount less than the effective amount for that compound, but which when combined with an effective or sub-therapeutic amount of another compound can produce a desired result, due to, for example, synergy in the resulting efficacious effects (e.g., therapeutic benefit) for the patient, or reduced side effects associated with the compounds administered to the patient.
  • Typical therapeutic amounts for a compound, as disclosed herein, can be ascertained from various publicly available sources (e.g., drugs.com,
  • Subtherapeutic amounts of a compound, as provided herein, are typically less than therapeutic amounts reported in the publicly available sources.
  • a “synergistically effective” therapeutic amount or “synergistically effective” amount of a compound is an amount which, when combined with an effective or subtherapeutic amount of another compound, produces a greater effect than when either of the two agents are used alone.
  • a synergistically effective therapeutic amount of a compound produces a greater effect when used in combination than the additive effects of each of the two compounds when used alone.
  • the term “greater effect” encompasses not only a reduction in symptoms of infection, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.
  • the term “sequentially” refers to administering more than one compounds at two different time points that are separated by more than 1 hour, e.g., about 2 hours, about 5 hours, 8 hours, 1 day,
  • treatment means obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease or symptom in a mammal, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to acquiring the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease or symptom, i.e., arresting its development; and/or (c) relieving the disease, i.e., causing regression of the disease.
  • the therapeutic agent may be administered before, during or after the onset of disease or injury.
  • the treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues.
  • the subject therapy will desirably be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.
  • mammals include, e.g., humans, non-human primates, rodents (e.g., rats; mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, and the like), etc. In some cases, the individual is a human.
  • inhibitors lipogenesis such as inhibitors of lipogenic enzymes, e.g., inhibitors of ACC1, ACC2, FASN, HMGCR, SCD1, DGAT1, or ACSS2, reduce SARS-CoV-2-mediated cell death in Vero-E6 cells, a standard in vitro COVID-19 infection model.
  • ACCl/2 inhibitors for example, TOFA, firsocostat, CP-640186, and PF-05175157, exhibit inhibition of viral cell killing at about 5 mM concentration by about 98%, 25%, 12%, and 10%, respectively.
  • FASN inhibitors for example, orlistat, C75, cerulenin, and GSK 2194069, exhibit inhibition of viral cell killing at about 5 mM concentration by about 20%, 10%, 9%, and 8%, respectively.
  • HMGCR inhibitors such as pitavastatin, simvastatin, atorvastatin, and rosuvastatin, exhibit inhibition of viral cell killing at 5 mM concentration by about 32%, 25%, 12%, and 10%, respectively.
  • the disclosure provides that inhibitors of lipogenic enzymes are useful for treating a SARS-CoV-2 infection.
  • AMP kinase is known to antagonize lipogenesis by inhibitory phosphorylation of ACC and the lipogenic transcription factor SREBP-1. Therefore, an inhibitor of lipogenesis can be an activator of 5’ AMP-activated protein kinase (AMPK).
  • AMPK AMP-activated protein kinase
  • the present disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of lipogenesis.
  • an inhibitor of lipogenesis is an inhibitor of a lipogenic enzyme, such as an inhibitor of ACC1, ACC2, FASN, HMGCR, SCD1, DGAT1, or ACSS2.
  • a lipogenic enzyme such as an inhibitor of ACC1, ACC2, FASN, HMGCR, SCD1, DGAT1, or ACSS2.
  • the present disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of ACC1 or ACC2.
  • the inhibitor of ACC1 or ACC2 is in some cases 5-(Tetradecyloxy)-2-furoic acid (TOFA).
  • TOFA has the following structure:
  • the present disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an analog of TOFA.
  • a method of the present disclosure comprises administering a compound of Formula I:
  • R 1 is R 1 is — O— R 2 , — O— R 3 — OR 2 , — O — R 3 — OC(O) — N(R 5 )R 6 , — O— R 3 — N(R 5 )R 6 , — O — R 3 — N(R 4 )C(O)0R 5 , — O — R 3 — C(O)0R 5 , — O— R 3 — C(O)N(R 5 )R 6 or — N(R 5 )S(O) 2 — R 4 ;
  • C7-Ci2alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms
  • C4-Ci2cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • Amino refers to the — NH2 radical.
  • Cyano refers to the — CN radical.
  • Hydroxy refers to the — NO2 radical.
  • Trifluoromethyl refers to the — CF 3 radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • an alkyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, — OR 14 , — OC(O) — R 14 , — N(R 14 )2, — C(O)R 14 , — C(O)OR 14 , — C(O)N(R 14 ) 2 , — N(R 14 )C(O)0R 16 , — N(R 14 )C(O)R 16 , — N(R 14 )S(O) t R 16 (where t is 1 to 2), — S(O) t OR 16 (where t is 1 to 2), — S(O) p R 16 (where p is 0 to 2), and — S(O)
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • an alkylene chain may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR 14 , — OC(O) — R 14 , — N(R 14 ) 2 , — C(O)R 14 , — C(O)0R 14 , — C(O)N(R 14 ) 2 , — N(R 14 )C(O)0R 16 , — N(R 14 )C(O)R 16 , — N(R 14 )S(O) t R 16 (where t is 1 to 2), — S(O) t 0R 16 (where t is 1 to 2), — S(O) p R 16 (where p is 0 to 2), and —
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from the group consisting of alkyl, akenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, heteroaryl, heteroarylalkyl, — R 15 — OR 14 , — R 15 — OC(O) — R 14 , — R 15 — N(R 14 ) 2 , — R 15 — C(O)R 14 , — R 15 — C(O)OR 14 , — R 15 — C(O)N(R 14 ) 2 , — R 15 — N(R 14 )C(O)0R 16 , — R 15 — N(R 14 )C(O)R 16 , — R 15 — N(R 14 )C(O)R 16
  • each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R 1S is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R 16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • Aralkyl refers to a radical of the formula — R b — R c where R b is an alkylene chain as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like.
  • the alkylene chain part of the aralkyl radical may be optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical may be optionally substituted as described above for an aryl group.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like.
  • cycloalkyl is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, — R 15 — OR 14 , — R 15 — 0C(O) — R 14 , — R 15 — N(R 14 ) 2 , — R 15 — C(O)R 14 , — R 15 — C(O)0R 14 , — R 15 — C(O)N(R 14 ) 2 , — R 15 — N(R 14 )C(O)0R 16 ,
  • Halo refers to bromo, chloro, fluoro or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2- bromoethyl, and the like.
  • the alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxo-l,3-dioxol-4yl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thi
  • heterocyclyl is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, — R 15 — OR 14 , — R 15 — 0C(O) — R 14 , — R 15 — N(R 14 ) 2 , — R 15 — C(O)0R 14 , — R 15 — C(O)0R 14 , — R 15 — C(O)N(R 14 ) 2 , — R 15 — N(R 14 )C(
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical may be optionally substituted as described above for heterocyclyl radicals.
  • Heterocyclylalkyl refers to a radical of the formula — R b R h where R b is an alkylene chain as defined above and R h is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene chain at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl,
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, — R 15 — OR 14 , — R 15 — OC(O)— R 14 , — R 15 — N(R 14 ) 2 , — R 15 — C(O)R 14 , — R 15 — C(O)0R 14 , — R 15 — C(O)N(R 14 ) 2 , — R 15 — N(R
  • R 15 — N C(OR 14 )R 14 , — R 15 — S(O) t OR 16 (where t is 1 to 2), — R 15 — S(O) p R 16 (where p is 0 to 2), and — R 15 — S(O) t N(R 14 ) 2 (where t is 1 to 2)
  • each R 14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl
  • each R is is independently a direct bond or a straight or branched alkylene or alkenylene chain
  • each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical may be optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula — R b Ri where R b is an alkylene chain as defined above and Ri is a heteroaryl radical as defined above.
  • the heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group.
  • the alkylene chain part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkylene chain.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • substituents on the functional group are also “optionally substituted” and so on, for the purposes of this invention, such iterations are limited to five, preferably such iterations are limited to two.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanes
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • a “pharmaceutical composition” refers to a formulation of a compound and a medium generally accepted in the art for the delivery of the biologically active compound to a mammal, e.g., humans.
  • a medium can include a pharmaceutically acceptable carrier, diluent, or excipient.
  • “Therapeutically effective amount” refers to that amount of a compound which, when administered to a mammal, e.g., a human, is sufficient to effect treatment of the disease or condition of interest in a mammal, e.g., a human, having the disease or condition.
  • the amount of a compound which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease or condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • a compound as disclosed herein, or a pharmaceutically acceptable salt thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • a compound as disclosed herein is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • one embodiment is a compound of formula (I) wherein: R 1 is — O — R 2 ; and R 2 is independently alkyl or heterocyclylalkyl.
  • one embodiment is a compound of formula (I) selected from: isopropyl 5-(tetradecyloxy)furan-2- carboxylate; 4-methylpentyl 5-(tetradecyloxy)furan-2-carboxylate; and (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl 5-(tetradecyloxy)furan-2-carboxylate.
  • R 1 is — O — R 2 ; and R 2 is haloalkyl or substituted aryl.
  • one embodiment is a compound of formula (I) selected from: 2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2- carboxylate; 2,2,2-trichloroethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-bromoethyl 5- (tetradecyloxy)furan-2-carboxylate; and 2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid.
  • R 1 is — O — R 3 — OR 2 ;
  • R 2 is optionally substituted heterocyclylalkyl; and
  • R 3 is an optionally substituted alkylene chain.
  • one embodiment is a compound of formula (I) which is 3-(tetrahydro-2H-pyran-2-yloxy)propyl 5-(tetradecyloxy)furan-2-carboxylate.
  • R 1 is — O — R 3 — OC(O) — N(R S )R 6 ; each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; R 3 is an optionally substituted alkylene chain; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or — R 3 — C(O)OR 3 ; and/or any R s and R 6 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl.
  • one embodiment is a compound of formula (I) selected from: 1- (benzyl(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 1-((2-ethoxy-2- oxoethyl)(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 4-(2S)-2-benzyl 1- (1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)pyrrolidine-l,2-dicarboxylate; 1-(4- phenylcyclohexanecarbonyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 1-(5- (tetradecyloxy)furan-2-carbonyloxy)ethyl 3-phenylpyrrolidine-1-carboxylate; 1-(5- (tetradecyloxy)
  • R 1 is — O — R 3 — N(R 5 )R 6 ;
  • R 3 is an optionally substituted alkylene chain; and
  • R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
  • R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or —
  • one embodiment is a compound of formula (I) selected from: 2- (dimethylamino)ethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-morpholinoethyl 5- (tetradecyloxy)furan-2-carboxylate; or 3-morpholinopropyl 5-(tetradecyloxy)furan-2- carboxylate.
  • R 1 is — O — R 3 — N(R 4 )C(O)0R 5 ;
  • R 3 is an optionally substituted alkylene chain; and
  • R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; and
  • R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.
  • R 1 is — O — R 3 — C(O)OR 5 ;
  • R 3 is an optionally substituted alkylene chain; and
  • R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.
  • R 1 is — O — R 3 — C(O)N(R 5 )R 6 ;
  • R 3 is an optionally substituted alkylene chain; and
  • R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and
  • R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or — R 3 — C(O)OR 4 ; or R 5 and R 6 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N- heteroaryl.
  • one embodiment is a compound of formula (I) selected from: 2-(benzyl(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; tert-butyl 4-(2-(5- tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazine- 1 -carboxylate; 2-(dicyclohexylamino)-2- oxoethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-(4-cyclohexylpiperazin-1-yl)-2-oxoethyl 5- (tetradecyloxy)furan-2-carboxylate; 2-oxo-2-(4-phenylpiperzin- 1 -yl)ethyl-5- (tetradecyloxy)furan-2-carboxylate; 2-((2-ethoxy-2-oxoethyl
  • R 1 is — N(R 5 )S(O) 2 — R 4 ;
  • R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • R 5 is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl.
  • one embodiment is a compound of formula (I) which is 5-(tetradecyloxy)-N-tosylfuran-2- carboxamide.
  • the pharmaceutical composition is a dermatological composition comprising a dermatologically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • Another inhibitor of ACC1 or ACC2 that can be administered using a method of the present disclosure is 2- [ 1 - [(2R)-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl] -5-methyl-6-( 1 ,3-oxazol-2- yl)-2,4-dioxothieno[2,3-d]pyrimidin-3-yl] -2-methylpropanoic acid (firsocostat)
  • an inhibitor of ACC1 or ACC2 is an inhibitor disclosed in the following patents and published patent applications: WO03072197, WO13098375, WO13098373, WO13092976, US20160108061, US201358004, WO13079668, WO13071169, WO13061962, WO13035827, WO13017600, WO12108478, WO12104428, WO12090219, WO12074126, US2012129833, WO12056372, WO12032014, WO12028676, WO12013716, WO12001107, US2011263562, WO11129399, DE102010008642, DE102010008643, WO11098433, WO11067306, WO10127208, WO10127212, WO10050445, US2010113473, JP2010043019, WO10002010, US2009253725, JP2009196966, WO09055682,
  • an inhibitor of a lipogenic enzyme is an inhibitor of HMGCR. Accordingly, in some cases, the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of HMGCR.
  • the inhibitor of HMGCR can be:
  • an inhibitor of HMGCR is as disclosed in the following patents and published patent applications: mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140; lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938; pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227; simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171; pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No.
  • an inhibitor of a lipogenic enzyme is an inhibitor of FASN. Accordingly, in some cases, a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2 comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising an inhibitor of FASN.
  • the inhibitor of FASN can be:
  • an inhibitor of FASN is as disclosed in the following published patent applications: US20200165265, US20200017458, US20190375780, US20190314376, US20190308969, US20190241533, US20180265479, US20170273964, US20150031742, US20100190856, US20100173982, US20090325877, US20050053631, and US20040024050. Any other suitable FASN inhibitor can also be used in the methods and compositions disclosed herein.
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of SCD1.
  • the inhibitor of SCD1 can be:
  • an inhibitor of SCD1 is an inhibitor disclosed in the following patents and published patent applications: WO 2016/141299, US 2013/0096181, US 2020/0061055, US 2019/0302121, US 2019/0046489, US 2018/0193325, US 2016/0200695, US 2011/0305781, US 2011/0021530, US 2008/0182851, and U.S. 9,233,102. Any other suitable SCD1 inhibitor can also be used in the methods and compositions disclosed herein.
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of DGAT1.
  • the inhibitor of DGAT 1 can be :
  • a combination of pradigastat or T863 can also be used.
  • an inhibitor of DGAT1 is an inhibitor disclosed in the following patents and published patent applications: WO2004047755, WO2005013907, WO2006082952, WO2006004200, WO2006044775, WO2006113919, WO2006120125, WO2006134317, WO2007060140, WO2007071966, WO2007137103, WO2007137107, WO07138304, WO07138311, WO07141502, WO07141517, WO07141538, WO07141545, WO07144571, WO2008011130, WO 2008011131, WO08129319, WO08067257, WO08134690,
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of ACSS2.
  • the inhibitor of ACSS2 can be 1-(2,3-dithiophen-2-ylquinoxalin-6-yl)-3-(2- methoxyethyl)urea (AK153939)
  • AK153939 1-(2,3-dithiophen-2-ylquinoxalin-6-yl)-3-(2- methoxyethyl)urea
  • an inhibitor of DGAT1 is an inhibitor disclosed in the following patents and published patent applications: US20170088523 and US20190263758. Any other suitable inhibitor can also be used in the methods and compositions disclosed herein.
  • AMPK is known to antagonize lipogenesis by inhibitory phosphorylation of ACC and the lipogenic transcription factor SREBP-1. Accordingly, an inhibitor of lipogenesis can be an activator of AMPK.
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an activator of AMPK.
  • the activator of AMPK can be:
  • An activator of AMPK can also be quercetin, a-lipoic acid, R-lipoic acid, resveratrol, guanidine, biguanidine, galegine, ginsenoside, curcumin, berberine, epigallocatechin gallate, theaflavin, hispidulin, or a salicylate.
  • an activator of AMPK is disclosed in the following patents and published patent applications: US20190046471, US 8,604,202, USB, 592, 594, US8,586,747. USB, 563, 746, US8,546,427, US8,563,729, US8,394,969, US8,329,914, US8,329,738, US20120172333,
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of a combination of two or more inhibitors of lipogenesis.
  • a combination of lipogenesis inhibitors can target either the same pathway (e.g. fatty acid synthesis) or different pathways (cholesterol and fatty acid synthesis) involved in lipogenesis.
  • Using a combination of lipogenesis inhibitors can have synergistic effects because of the interconnected nature of different pathways, as described in Figure 2 of Horton et al. (2002), J. Clin. Invest.; 109(9): 1125-1131.
  • a combination of inhibitors of lipogenesis can comprise an inhibitor of a lipogenic enzyme and an activator of AMPK.
  • a combination of inhibitors of lipogenesis can comprise any combination of two or more of the following: 1) ACC1 inhibitor, 2) ACC2 inhibitor, 3) FASN inhibitor, 4) HMGCR inhibitor, 5) SCD1 inhibitor, 6) DGAT1 inhibitor, 7) ACSS2 inhibitor, or 9) AMPK activator.
  • each inhibitor can be administered at a dose that is lower than the dose of the inhibitor that is therapeutically effective when administered alone because the two or inhibitors of lipogenesis synergistically inhibit the effects of the SARS-CoV-2 infection, for example, cytopathic effect of the virus.
  • an individual suitable for treatment with a method of the present disclosure is infected with SARS-Cov2, and does not have any co-morbidity associated with increased risk of severe illness or death from Covid-19.
  • an individual suitable for treatment with a method of the present disclosure does not have chronic kidney disease, chronic obstructive pulmonary disease (COPD), an immunocompromised state, obesity, coronary artery disease, a cardiomyopathy, sickle cell disease, or type 2 diabetes.
  • COPD chronic obstructive pulmonary disease
  • an individual suitable for treatment with a method of the present disclosure is infected with SARS- Cov2 and has one or more of: chronic kidney disease, COPD, an immunocompromised state, obesity, coronary artery disease, a cardiomyopathy, sickle cell disease, or type 2 diabetes.
  • an individual suitable for treatment with a method of the present disclosure has been diagnosed as being infected with SARS-CoV2. In some cases, an individual suitable for treatment with a method of the present disclosure has been diagnosed as being infected with SARS-CoV2 and is asymptomatic for Covid-19. In some cases, an individual suitable for treatment with a method of the present disclosure has been diagnosed as being infected with SARS-CoV2, and exhibits one or more symptoms of Covid-19; e.g., the individual exhibits one or more of fever, chills, cough, shortness of breath, difficulty breathing, fatigue, muscle aches, sore throat, nausea, and diarrhea.
  • an inhibitor of lipogenesis is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of lipogenesis when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of lipogenesis is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of ACC1 is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of ACC1 when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of ACC1 is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of ACC2 is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of ACC2 when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of ACC2 is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of HMGCR is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of HMGCR when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of HMGCR is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of FASN is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of FASN when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of FASN is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of SCD1 is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of SCD1 when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of SCD1 is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of DGAT1 is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of DGAT1 when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of DGAT1 is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an inhibitor of ACSS2 is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an inhibitor of ACSS2 when the patient contracted the SARS-CoV-2 infection. Therefore, an inhibitor of ACSS2 is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • an activator of AMPK is administered for treating a SARS-CoV-2 infection in a patient, wherein the patient was not receiving a therapy of an activator of AMPK when the patient contracted the SARS-CoV-2 infection. Therefore, an activator of AMPK is administered to the patient for the treatment of the SARS-CoV-2 infection.
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of lipogenesis in combination with an RdRp inhibitor.
  • An inhibitor of lipogenesis can be an inhibitor of a lipogenic enzyme, such as an inhibitor of ACC1, ACC2, HMGCR, FASN, SCD1, DGAT1, or ACSS2.
  • An inhibitor of lipogenesis can also be an activator of AMPK.
  • RdRp inhibitor Any suitable RdRp inhibitor can be used in the methods disclosed herein.
  • Certain nonlimiting examples of RdRp inhibitors include sofosbuvir, remdesivir, ribavirin, favipiravir, pimodivir, and baloxavir.
  • the disclosure provides a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of lipogenesis and/or an RdRp inhibitor, in further combination with an anti-inflammatory agent.
  • an anti-inflammatory agent can be used in the methods disclosed herein.
  • an anti-inflammatory agent is a steroidal anti-inflammatory agent.
  • steroidal anti-inflammatory agents include beclomethasone, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.
  • an anti-inflammatory agent is a non-steroidal anti-inflammatory agent.
  • non-steroidal anti-inflammatory agents include aceclofenac, acetylsalicylic acid, bufexamac, diclofenac, etodolac, fenclofenac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamicacid, mefenamicacid, naproxen, niflumic acid, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulfasalazine, sulindac, suprofen, tenoxicam, tiaprofenic acid, tolfenamic acid, nabumetone, celecoxib, and andetoricoxib.
  • an inhibitor of lipogenesis and/or an RdRp inhibitor and/or an antiinflammatory agent are administered simultaneous with each other.
  • an inhibitor of lipogenesis and/or an RdRp inhibitor and/or an anti-inflammatory agent can be in a single or separate compositions.
  • each of an inhibitor of lipogenesis, an RdRp inhibitor, and an antiinflammatory agent is administered sequentially.
  • any two of an inhibitor of lipogenesis, an RdRp inhibitor, and an antiinflammatory agent are administered simultaneously with each other, while the remaining third compound is administered sequentially from the other two.
  • the compounds that are administered simultaneously can be administered in a single formulation or separate formulations.
  • An inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or antiinflammatory agent can be administered via any suitable route of administration. Suitable routes of administration include oral, rectal, nasal, pulmonary, topical, vaginal, subcutaneous, intramuscular, intraperitoneal, intravenous, intradermal, intrathecal, and epidural. The preferred route may vary with, for example, the condition of the recipient of the combination of the compounds.
  • an inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or anti-inflammatory agent can be administered via pulmonary route, such as via inhalation.
  • the different compounds can be administered via the same or different routes.
  • compositions comprising any combination of an inhibitor of lipogenesis, RdRp inhibitor, and anti-inflammatory agent are envisioned.
  • a pharmaceutical composition comprising an inhibitor of lipogenesis in combination with an RdRp inhibitor and/or an anti-inflammatory agent.
  • a pharmaceutical composition comprises an inhibitor of lipogenesis and an RdRp inhibitor.
  • a pharmaceutical composition comprises an inhibitor of lipogenesis and an anti-inflammatory agent.
  • a pharmaceutical composition comprises an inhibitor of lipogenesis, an RdRp inhibitor, and an anti-inflammatory agent.
  • a pharmaceutical composition can comprise any inhibitor of lipogenesis identified in this disclosure and any RdRp inhibitor identified in this disclosure. Similarly, a pharmaceutical composition can comprise any inhibitor of lipogenesis identified in this disclosure and any antiinflammatory agent identified in this disclosure. Moreover, a pharmaceutical composition can comprise any inhibitor of lipogenesis identified in this disclosure and any RdRp inhibitor identified in this disclosure and any anti-inflammatory agent identified in this disclosure.
  • An inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or antiinflammatory agent of the present disclosure can be incorporated into a variety of formulations can be used for treating SARS-CoV2 infection in a patient.
  • the disclosure provides the formulation comprises a combination of two or more inhibitors of lipogenesis.
  • a combination of lipogenesis inhibitors can target either the same pathway (e.g. fatty acid synthesis) or different pathways (cholesterol and fatty acid synthesis) involved in lipogenesis.
  • a combination of inhibitors of lipogenesis can comprise an inhibitor of a lipogenic enzyme and an activator of AMPK.
  • a combination of inhibitors of lipogenesis can comprise any combination of two or more of the following: 1) ACC1 inhibitor, 2) ACC2 inhibitor, 3) FASN inhibitor, 4) HMGCR inhibitor, 5) SCD1 inhibitor, 6) DGAT1 inhibitor, 7) ACSS2 inhibitor, or 9) AMPK activator.
  • such compounds can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, lotions, and aerosols.
  • administration of the compounds can be achieved in various ways, including oral, vaginal, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, or intratracheal administration.
  • an inhibitor of lipogenesis can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • An inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or antiinflammatory agent can be formulated into preparations for injections by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
  • solubilizers isotonic agents
  • suspending agents emulsifying agents, stabilizers and preservatives.
  • An inhibitor of lipogenesis can be utilized in aerosol formulation to be administered via inhalation.
  • the compounds of the present invention can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.
  • An inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or antiinflammatory agent can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • the compounds of the present invention can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage forms may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more compounds of the present invention.
  • unit dosage forms for injection or intravenous administration may comprise the compound or compounds of the present invention in a composition as a solution in sterile water, normal saline, or another pharmaceutically acceptable carrier.
  • Implants for sustained release formulations are well-known in the art. Implants are formulated as microspheres, slabs, etc. with biodegradable or non-biodegradable polymers. For example, polymers of lactic acid and/or glycolic acid form an erodible polymer that is well- tolerated by the host.
  • An implant containing an inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or anti-inflammatory agent can be placed in proximity of the respiratory system and/or gastrointestinal system, so that the local concentration the compounds is increased relative to the rest of the body.
  • unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of compounds of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
  • the specifications for the unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with the compound in the host.
  • the pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, are readily available to the public.
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • Typical dosages for administration range from 0.1 ⁇ g to 100 milligrams per kg weight of subject per administration.
  • a single dose can include from about 1 ⁇ g to about 10 g, from about 10 ⁇ g to about 25 ⁇ g, from about 25 ⁇ g to about 50 ⁇ g, from about 50 ⁇ g to about 100 ⁇ g, from about 100 ⁇ g to about 500 ⁇ g, from about 500 ⁇ g to about 1 mg, from about 1 mg to about 5 mg, or from about 5 mg to about 10 mg, of an inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or anti-inflammatory agent.
  • a dosage can be selected to produce the concentration of the active compound or compounds in the host blood within the first 24-48 hours after administration in the range of about 0.1-1000 mM, about 0.5-500 mM, about 1-100 pM, or about 5-50 pM.
  • a dosage can be selected to produce the concentration of an inhibitor of lipogenesis in the host blood within the first 24-48 hours after administration in the range of about 0.1-1000 pM, about 0.5-500 pM, about 1-100 pM, or about 5-50 pM.
  • a typical dosage may be one tablet taken from two to six times daily, or one time- release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect may be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • dose levels can vary as a function of the specific inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or antiinflammatory agent, the severity of the symptoms and the susceptibility of the subject to side effects.
  • An inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or antiinflammatory agent will in some cases be administered to a patient by means of a pharmaceutical delivery system for the inhalation route.
  • the active compound or compounds may be formulated in a form suitable for administration by inhalation.
  • the inhalational mode of administration provides the advantage that the inhaled drug can bypass the blood-brain barrier.
  • the pharmaceutical delivery system is one that is suitable for respiratory therapy by delivery of an active compound or compounds to mucosal linings of the bronchi.
  • This embodiment can utilize a system that depends on the power of a compressed gas to expel the active compound or compounds from a container.
  • An aerosol or pressurized package can be employed for this purpose.
  • aerosol is used in its conventional sense as referring to very fine liquid or solid particles carries by a propellant gas under pressure to a site of therapeutic application.
  • the aerosol contains an inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or antiinflammatory agent, which can be dissolved, suspended, or emulsified in a mixture of a fluid carrier and a propellant.
  • the aerosol can be in the form of a solution, suspension, emulsion, powder, or semi-solid preparation. Aerosols employed in the present invention are intended for administration as fine, solid particles or as liquid mists via the respiratory tract of a patient.
  • Suitable propellants include, but are not limited to, hydrocarbons or other suitable gas.
  • the dosage unit may be determined by providing a value to deliver a metered amount.
  • An inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or antiinflammatory agent can also be formulated for delivery with a nebulizer, which is an instrument that generates very fine liquid particles of substantially uniform size in a gas.
  • a nebulizer is an instrument that generates very fine liquid particles of substantially uniform size in a gas.
  • a liquid containing the active compound or compounds is dispersed as droplets.
  • the small droplets can be carried by a current of air through an outlet tube of the nebulizer. The resulting mist penetrates into the respiratory tract of the patient.
  • an inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or anti-inflammatory agent can be formulated in basically three different types of formulations for inhalation.
  • an active compound or compounds can be formulated with low boiling point propellants.
  • Such formulations are generally administered by conventional meter dose inhalers (MDIs).
  • MDIs meter dose inhalers
  • conventional MDIs can be modified so as to increase the ability to obtain repeatable dosing by utilizing technology which measures the inspiratory volume and flow rate of the patient.
  • an inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or anti-inflammatory agent can be formulated in aqueous or ethanolic solutions and delivered by conventional nebulizers.
  • solution formulations are aerosolized using devices and systems such as disclosed within U.S. Pat. Nos. 5,497,763; 5,544,646; 5,718,222; and 5,660,166.
  • An inhibitor of lipogenesis optionally, in combination with RdRp inhibitor and/or antiinflammatory agent can be formulated into dry powder formulations. Such formulations can be administered by simply inhaling the dry powder formulation after creating an aerosol mist of the powder. Technology for carrying such out is described within U.S. Pat. Nos. 5,775,320 and 5,740,794.
  • Aspect 1 A method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2, the method comprising administering to the patient a therapeutically effective amount of an inhibitor of lipogenesis.
  • Aspect 2 The method of aspect 1, wherein the inhibitor of lipogenesis is an inhibitor of a lipogenic enzyme.
  • Aspect 3 The method of aspect 2, wherein the inhibitor of lipogenic enzyme is an inhibitor of acetyl-CoA carboxylase 1 (ACC1), acetyl-CoA carboxylase 2 (ACC2), fatty acid synthase (FASN), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), stearoyl-CoA desaturase-1 (SCD1), Diacylglycerol O-Acyltransferase 1 (DGAT1), or Acetyl-CoA synthetase 2 (ACSS2).
  • ACC1 acetyl-CoA carboxylase 1
  • ACC2 acetyl-CoA carboxylase 2
  • FASN fatty acid synthase
  • HMGCR 3-hydroxy-3-methyl-glutaryl-CoA reductase
  • SCD1 stearoyl-CoA desaturase-1
  • DGAT1 Diacylglycerol O-Acyltransferas
  • Aspect 4 The method of aspect 2 or 3, wherein the inhibitor of the lipogenic enzyme is an inhibitor of HMGCR.
  • Aspect 5 The method of aspect 4, wherein the inhibitor of HMGCR is atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitavastatin, or L-659699.
  • Aspect 6 The method of aspect 2 or 3, wherein the inhibitor of the lipogenic enzyme is an inhibitor of ACC1 or ACC2.
  • Aspect 7 The method of aspect 6, wherein the inhibitor of ACC1 or ACC2 is 5-
  • TOFA Tetradecyloxy-2-furoic acid
  • firsocostat CP-640186
  • PF-05175157 PF-05175157
  • MK-4074 Metradecyloxy-2-furoic acid
  • Aspect 8 The method of aspect 2 or 3, wherein the inhibitor of the lipogenic enzyme is an inhibitor of FASN.
  • Aspect 9 The method of aspect 8, wherein the inhibitor of FASN is C-75, orlistat, cerulenin, TVB-3166, FT113, or GSK 2194069.
  • Aspect 10 The method of aspect 2 or 3, wherein the inhibitor of the lipogenic enzyme is an inhibitor of SCD1.
  • Aspect 11 The method of aspect 10, wherein the inhibitor of SCD1 is A939572,
  • Aspect 12 The method of aspect 2 or 3, wherein the inhibitor of the lipogenic enzyme is an inhibitor of DGAT1.
  • Aspect 13 The method of aspect 12, wherein the inhibitor of DGAT is pradigastat or T863.
  • Aspect 14 The method of aspect 2 or 3, wherein the inhibitor of the lipogenic enzyme is an inhibitor of ACSS2.
  • Aspect 15 The method of aspect 14, wherein the inhibitor of ACSS2 is AK153939.
  • Aspect 16 The method of aspect 1, wherein the inhibitor of lipogenesis is an activator of 5’ AMP-activated protein kinase (AMPK).
  • AMPK AMP-activated protein kinase
  • Aspect 17 The method of aspect 16, wherein the activator of AMPK is phenformin, A769662, AICAR, or metformin.
  • Aspect 18 The method of any of preceding aspects, comprising administering the inhibitor of lipogenesis via the oral, intranasal, vaginal, rectal, intramuscular, intravenous, intraperitoneal, subcutaneous, or pulmonary route.
  • Aspect 19 The method of any of preceding aspects, comprising administering the inhibitor of lipogenesis via the pulmonary route.
  • Aspect 20 The method of any of preceding aspects, wherein the effective amount of the inhibitor of lipogenesis produces at least 5 mM concentration of the inhibitor within the viral infected cells of the patient.
  • Aspect 21 The method of any of preceding aspects, further comprising administering to the patient an RNA-dependent RNA polymerase (RdRp) inhibitor.
  • RdRp RNA-dependent RNA polymerase
  • Aspect 22 The method of aspect 21, wherein the RdRp inhibitor is sofosbuvir, remdesivir, ribavirin, favipiravir, pimodivir, or baloxavir.
  • Aspect 23 The method of any of preceding aspects, further comprising administering to the patient an anti-inflammatory agent.
  • Aspect 24 The method of aspect 23, wherein the anti-inflammatory agent is a steroidal anti-inflammatory agent.
  • Aspect 25 The method of aspect 24, wherein the steroidal anti-inflammatory agent is beclomethasone, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone.
  • the steroidal anti-inflammatory agent is beclomethasone, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone.
  • Aspect 26 The method of aspect 23, wherein the anti-inflammatory agent is a non steroidal anti-inflammatory agent.
  • Aspect 27 The method of aspect 26, wherein the non-steroidal anti-inflammatory agent is aceclofenac, acetylsalicylic acid, bufexamac, diclofenac, etodolac, fenclofenac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamicacid, mefenamicacid, naproxen, niflumic acid, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulfasalazine, sulindac, suprofen, tenoxicam, tiaprofenic acid, tolfenamic acid, nabumetone, celecoxib, or andetoricoxib.
  • the non-steroidal anti-inflammatory agent is aceclofenac, acetylsalicylic acid, buf
  • a pharmaceutical composition comprising an inhibitor of lipogenesis, optionally, in combination with RdRp inhibitor and/or anti-inflammatory agent, and a pharmaceutically acceptable carrier.
  • Aspect 29 The pharmaceutical composition of aspect 28, wherein the pharmaceutical composition is suitable for administration via oral, intranasal, vaginal, rectal, intramuscular, intravenous, intraperitoneal, subcutaneous, or pulmonary route.
  • Aspect 30 The pharmaceutical composition of aspect 28 or 29, comprising an inhibitor of lipogenesis and an RdRp inhibitor.
  • Aspect 31 The pharmaceutical composition of any of aspects 20 to 22, comprising an inhibitor of lipogenesis, an RdRp inhibitor, and an anti-inflammatory agent.
  • Aspect 32 The pharmaceutical composition of any of aspects 28 to 31, wherein the inhibitor of lipogenesis is an inhibitor of a lipogenic enzyme.
  • Aspect 33 The pharmaceutical composition of aspect 32, wherein the inhibitor of the lipogenic enzyme is an inhibitor of HMGCR.
  • Aspect 34 The pharmaceutical composition of aspect 33, wherein the inhibitor of
  • HMGCR is atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitavastatin, or L-659699.
  • Aspect 35 The pharmaceutical composition of aspect 32, wherein the inhibitor of the lipogenic enzyme is an inhibitor of ACC1 or ACC2.
  • Aspect 36 The pharmaceutical composition of aspect 35, wherein the inhibitor of
  • ACC1 or ACC2 is 5-(Tetradecyloxy)-2-furoic acid (TOFA), firsocostat, CP-640186, PF- 05175157, or MK-4074.
  • Aspect 37 The pharmaceutical composition of aspect 32, wherein the inhibitor of the lipogenic enzyme is an inhibitor of FASN.
  • Aspect 38 The pharmaceutical composition of aspect 37, wherein the inhibitor of
  • FASN is C-75, orlistat, cerulenin, TVB-3166, FT113, or GSK 2194069.
  • Aspect 39 The pharmaceutical composition of aspect 32, wherein the inhibitor of the lipogenic enzyme is an inhibitor of SCD1.
  • Aspect 40 The pharmaceutical composition of aspect 39, wherein the inhibitor of
  • SCD1 is A939572, MF438, PluriSIn #1, or MK-8245.
  • Aspect 41 The pharmaceutical composition of aspect 32, wherein the inhibitor of the lipogenic enzyme is an inhibitor of DGAT1.
  • DGAT is pradigastat or T863.
  • Aspect 43 The pharmaceutical composition of aspect 32, wherein the inhibitor of the lipogenic enzyme is an inhibitor of ACSS2.
  • Aspect 44 The pharmaceutical composition of aspect 43, wherein the inhibitor of
  • ACSS2 is AK153939.
  • Aspect 45 The pharmaceutical composition of any of aspects 28 to 31, wherein the inhibitor of lipogenesis is an activator of AMPK.
  • Aspect 46 The pharmaceutical composition of aspect 45, wherein the activator of
  • AMPK is phenformin, A769662, AICAR, or metformin.
  • Aspect 47 The pharmaceutical composition of any of aspects 28 to 46, wherein the
  • RdRp inhibitor is sofosbuvir, remdesivir, ribavirin, favipiravir, pimodivir, or baloxavir.
  • Aspect 48 The pharmaceutical composition of any of aspects 28 to 47, wherein the anti-inflammatory agent is a steroidal anti-inflammatory agent.
  • Aspect 49 The pharmaceutical composition of aspect 48, wherein the steroidal anti-inflammatory agent is beclomethasone, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone.
  • the steroidal anti-inflammatory agent is beclomethasone, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone.
  • Aspect 50 The pharmaceutical composition of any of aspects 28 to 49, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent.
  • Aspect 51 The pharmaceutical composition of aspect 50, wherein the non-steroidal anti-inflammatory agent is aceclofenac, acetylsalicylic acid, bufexamac, diclofenac, etodolac, fenclofenac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamicacid, mefenamicacid, naproxen, niflumic acid, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulfasalazine, sulindac, suprofen, tenoxicam, tiaprofenic acid, tolfenamic acid, nabumetone, celecoxib, or andetoricoxib.
  • the non-steroidal anti-inflammatory agent is aceclofenac, acetylsalicylic acid,
  • a method of treating a SARS-CoV-2 infection in a patient infected with SARS-CoV-2 comprising administering to the patient a therapeutically effective amount of a compound of formula I:
  • R 1 is R 1 is — O— R 2 , — 0— R 3 — OR 2 , — 0 — R 3 — OC(O) — N(R 5 )R 6 , — O— R 3 — N(R 5 )R 6 , — O — R 3 — N(R 4 )C(O)0R 5 , — O — R 3 — C(O)OR 5 , — 0— R 3 — C(O)N(R 5 )R 6 or — N(R 5 )S(O) 2 — R 4 ;
  • each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • each R 3 is independently an optionally substituted alkylene chain
  • R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • each R 5 is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
  • each R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or — R 3 — C(O)OR 4 ; or any R 5 and R 6 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; as a single stereoisomer or as a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Aspect 53 The method of aspect 52, wherein:
  • R 1 is — O— R 2 , or — O — R 3 — C(O)N (R 5 )R 6 ;
  • R 2 is haloalkyl or aryl optionally substituted with -COOH
  • R 3 is independently an optionally substituted alkylene chain
  • R 4 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
  • R 5 is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl;
  • R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or — R 3 — C(O)OR 4 ; or any R 5 and R 6 , together with the nitrogen to which they are both attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl; as a single stereoisomer or as a mixture thereof or as part of a pharmaceutical composition.
  • Aspect 54 The method of aspect 52, wherein the compound of formula I has the structure:
  • Aspect 55 The method of any one of aspects 52-54, wherein the compound is administered via an oral, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous, or pulmonary route.
  • Aspect 56 The method of any one of aspects 52-54, wherein the compound is administered via a pulmonary route.
  • Standard abbreviations may be used, e.g., min, minute(s); h or hr, hour(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly); and the like.
  • Vero-E6 cells were infected with SARS-CoV-2 virus, a standard in vitro COVID-19 infection model.
  • the infected cells were cultured in the presence of various inhibitors of lipogenic enzymes.
  • the effect of the inhibitors on the cytopathic effect of the vims as well as on the cell viability were studied. The relevant findings are provided in FIG. 1.
  • FIG. 1 shows that inhibitors of lipogenic enzymes, e.g., ACC1, ACC2, FASN, or HMGCR, reduce SARS-CoV-2-mediated cell death in Vero-E6 cells.
  • lipogenic enzymes e.g., ACC1, ACC2, FASN, or HMGCR
  • ACCl/2 inhibitors exhibited inhibition of viral cell killing at 5 mM concentration as follows: TOFA (97.85%), firsocostat (23.65%), CP-640186 (11.65%), PF-05175157 (9.05%).
  • FASN inhibitors exhibited inhibition of viral cell killing at 5 mM concentration as follows: Orlistat (20.15%), C75 (10.65%), Cerulenin (8.695%), GSK 2194069 (7.595%).
  • HMGCR inhibitors exhibited inhibition of viral cell killing at 5 mM concentration as follows: Pitavastatin (32.05%), Simvastatin (25.25%), Atorvastatin (12%), Rosuvastatin (9.585%).
  • Calu3 cells were infected with SARS-CoV-2 virus.
  • the infected cells were cultured in the presence of various inhibitors of lipogenic enzymes.
  • the effect of the inhibitors on the cytopathic effect (CPE) of the virus as well as on the cell viability were studied.
  • the relevant findings are provided in FIG. 2.
  • Example 3 Effect of inhibitors on Vero and Calu-3 cells in vitro
  • Vero and Calu-3 cells were infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 0.05.
  • TOFA was dissolved in dimethylsulfoxide (DMSO) and added to the culture medium. After infection and treatment with TOFA, cells were cultured for 72 hrs (Vero E6) or
  • Example 4 Effect of TOFA on SARS-CoV-2 in various cell lines in vitro [00265] Vero E6 cells and Huh-7 cells were infected with SARS-CoV-2 at an MOI of 0.05; and Calu-3 cells were infected with SARS-CoV-2 at MOI of 0.1. TOFA was dissolved in DMSO and added to the culture medium. After infection with SARS-CoV-2 and treatment with TOFA, cells were cultured for 24 hours (Huh-7 and Vero E6) or 48 hours (Calu-3). After the 24-hour or 48- hour culture periods, RNA was extracted from both cells and culture media.
  • RT-qPCR Reverse transcription-quantitative polymerase chain reaction
  • Example 5 Effect of TOFA on SARS-CoV-2 variants
  • Huh-7 cells were infected with SARS-CoV-2 variants B.1.117 (alpha), B.1.427. B.1.429, D614G, B.1.351 (beta), P.l (gamma), B.1.617.2 (delta), or WA1 at an MOI of 0.05.
  • TOFA was dissolved in DMSO and added to the culture medium. After infection with the SARS-CoV-2 variants and treatment with TOFA, the cells were cultured for 48 hours.
  • Example 6 RNA-Seq analysis of SARS-CoV-2-infected Huh-7 cells
  • Huh-7 cells were infected with SARS-CoV-2 at an MOI of 0.05.
  • TOFA was dissolved in DMSO and added to the culture medium. After infection with SARS-CoV-2 and treatment with TOFA, the cells were cultured for 24 hours. After the 24-hour culture period, RNA was extracted from the cells. The extracted RNA was used for RNA-seq library preparation using polyA tail capturing. The results are shown in FIG. 6A-6C.
  • SARS-CoV-2-induced expression profile change was defined by comparing the infected group with the uninfected control group (1,341 up-regulated and 456 down-regulated genes in infected Huh-7 cells, FIG. 6B). It was then confirmed that SARS-CoV- 2-induced expression profile changes in host cells were robustly rescued by TOFA treatment (FIG. 6C).
  • Example 7 In vivo effect of TOFA on SARS-CoV-2 viral titer
  • the effect of TOFA on SARS-CoV-2 viral titer was determined in hamsters. Hamsters were infected with SARS-CoV-2 strain WA1/2019. The hamsters were inoculated with 10 TCID 50 /4O m ⁇ by intranasal administration. At various time points, the hamsters were treated with TOFA. TOFA was suspended in an aqueous solution comprising 5% NMP/20% PEG200. The TOFA solution was administered to the hamsters by oral gavage. At Day 4 after inoculation, the left lobe of the lung was collected and lysed. The lysate was used in a TCID50 (50% tissue culture infectious dose) assay to determine the viral load. The results are shown in FIG. 7. As shown in FIG. 7, TOFA treatment reduced the viral titer.

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Abstract

La présente divulgation concerne des méthodes de traitement d'une infection par le SARS-CoV-2 chez un patient infecté par le SARS-CoV-2. La présente divulgation concerne des compositions pharmaceutiques comprenant un inhibiteur de lipogenèse, éventuellement, combiné à un inhibiteur de RdRp et/ou à un agent anti-inflammatoire.
PCT/US2021/038908 2020-06-29 2021-06-24 Méthodes de traitement d'une infection par le sars-cov-2 à l'aide d'inhibiteurs de la lipogenèse WO2022005871A1 (fr)

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CN117695276A (zh) * 2024-02-06 2024-03-15 山东大学 脂肪酸合酶抑制剂c75在制备抗白斑综合征药物中的应用

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EP4268810A1 (fr) * 2022-04-28 2023-11-01 Eberhard Karls Universität Tübingen, Medizinische Fakultät Agent antiviral à large spectre
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CN115337308A (zh) * 2022-07-15 2022-11-15 山东省农业科学院家禽研究所（山东省无特定病原鸡研究中心） Acss2抑制剂在制备抗h1n1亚型猪流感病毒药物中的应用
CN115337308B (zh) * 2022-07-15 2024-03-22 山东省农业科学院家禽研究所（山东省无特定病原鸡研究中心） Acss2抑制剂在制备抗h1n1亚型猪流感病毒药物中的应用
CN117695276A (zh) * 2024-02-06 2024-03-15 山东大学 脂肪酸合酶抑制剂c75在制备抗白斑综合征药物中的应用
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