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WO2025170898A1 - Inhibiteurs de fixation du sars-cov-2 et leur utilisation thérapeutique - Google Patents

Inhibiteurs de fixation du sars-cov-2 et leur utilisation thérapeutique

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Publication number
WO2025170898A1
WO2025170898A1 PCT/US2025/014432 US2025014432W WO2025170898A1 WO 2025170898 A1 WO2025170898 A1 WO 2025170898A1 US 2025014432 W US2025014432 W US 2025014432W WO 2025170898 A1 WO2025170898 A1 WO 2025170898A1
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WO
WIPO (PCT)
Prior art keywords
independently
compound
ace2
subject
tmprss2
Prior art date
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English (en)
Inventor
Thomas Bannister
Michael Farzan
Hyeryun CHOE
Lizhou ZHANG
Huihui Mu
Louis SCAMPAVIA
Yuka Otsuka
Timothy SPICER
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University of Florida
University of Florida Research Foundation Inc
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University of Florida
University of Florida Research Foundation Inc
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Publication of WO2025170898A1 publication Critical patent/WO2025170898A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to centuries, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Attachment of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2 (ACE2). To date there remains no FDA approved commercially available SARS-CoV-2 attachment inhibitors. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus attachment onto target cells.
  • ACE2 angiotensin-converting enzyme 2
  • ACE2 angiotensin converting enzyme 2
  • TMPRSS2 transmembrane protease, serine 2
  • R 1 is H or halo
  • R 2 is a 5-7 membered heteroaryl, wherein the heteroaryl contains 1 , 2, or 3 heteroatoms selected from N, 0, and S, and wherein the heteroaryl is optionally substituted with 1 , 2, or 3 R a
  • R 3 is a Ci salkyl-N(R a )2 or Co ealkylene-5-7 membered heterocycle, wherein the heterocycle contains 1 , 2, or 3 heteroatoms selected from N, 0, and S; and wherein the heterocycle is optionally substituted with 1 , 2, or 3 R a
  • W is
  • R 1 is a Co-eal kylene, wherein the alkylene is optionally substituted with 1 , 2, or 3 Ci-ealkyl or NH2
  • R 2 is a 5-10 membered aryl or a 5-10 membered heterocycle, wherein the heterocycle contains 1 , 2, or 3 heteroatoms selected from N, 0, and S, and wherein the aryl and the heterocycle are optionally substituted with 1 , 2, or 3 R a
  • R a is halo, Co-ealkyleneCs-ioaryl.
  • kits for treating or preventing SARS-CoV-2 in a subject comprising administering to the subject an effective amount of one or more compounds having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), and pharmaceutically acceptable salts of any of the foregoing.
  • FIGURE 2 shows the firefly luciferase (Flue) luminescence and NanoLuc® luciferase (NIuc) luminescence of hACE2-H1299 cells that were screened.
  • R 2 and R 3 are each independently OH, Ci-ealkyl, Ci-ealkylhydroxy, or Ci-ealkaryl, wherein when both R 2 and R 3 are each Ci-ealkyl the alkyl substituents may be taken together to form a 5-7 membered heterocycle, wherein the heterocycle may optionally contain 1 , 2, or 3 additional heteroatoms selected from N, 0, and S;
  • R 4 and R 4 ’ are each independently H or halo
  • R 1 and R 1 ' are each independently H or CH3. In various cases, R 1 and R 1 ' are each independently H. In various cases, R 1 and R 1 ' are each independently CH3. In various cases, R 2 and R 3 are each independently Ci-ealkyl or Ci-galkaryl, wherein when both R 2 and R 3 are each Ci-ealkyl the alkyl substituents may be taken together to form a 5-7 membered heterocycle. In various cases R 2 and R 3 are each independently Cisalkyl. In various cases, the alkyl groups taken together form a 6 membered heterocycle. In various cases, the alkyl groups taken together form a 7 membered heterocycle.
  • R 2 and R 3 can be a Cisalkyl and the other of R 2 and R 3 can be a Ci-salkaryl.
  • R 4 and R 4 ’ each independently H or Cl.
  • R 4 and R 4 ’ are each independently H.
  • R 4 and R 4 ’ each independently Cl.
  • R 5 is H, Ci-salkyl, or a 6 membered aryloxy.
  • R 5 is H.
  • R 5 is Cisalkyl.
  • R 5 is Csalkyl.
  • R 5 is /-propyl.
  • R 5 is phenoxy.
  • R 1 is H or halo
  • R 2 is a 5-7 membered heteroaryl, wherein the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, 0, and S, and wherein the heteroaryl is optionally substituted with 1 , 2, or 3 R a ;
  • R 3 is a Ci-6alkyl-N(R a )2 or Co-ealkylene-5-7 membered heterocycle, wherein the heterocycle contains 1, 2, or 3 heteroatoms selected from N, 0, and S; and wherein the heterocycle is optionally substituted with 1, 2, or 3 R a ;
  • W is CH 2 or O
  • R 1 is H or F. In various cases, R 1 is H. In various cases, R 1 is F.
  • R 2 is 4-pyridi ne, 4-pyrazole, or 2-methyl-4-imidazole. In various cases R 2 is 4-pyridine or 4-pyrazole. In various cases, R 2 is 4-pyrazole.
  • R 3 is N, N-dimethyl-2-ethylene, N-benzyl-N-methyl-2-ethylene, N- methyl-3-pyrrolidine, or 1 -pyrrolidine. In various cases, R 3 is N, N-dimethyl-2-ethylene.
  • W is 0.
  • X is CH2. In various cases, Y is CH2 or NR a .
  • Y is CH2. In various cases, Y is NR a . In various cases, R a is H or C2alkyl. In various cases R a is H. In various cases Z is CH2. In various cases, Z is 0. In various cases, R 4 is H and R 4 ’ are both H. In various cases, R 4 is H and R 4 ’ is F. In various cases, R 4 is H and R 4 ’ is CH3 In various cases, R 4 is H and R 4 ’ is OCH3.
  • R 1 is Ci-2alkylene optionally substituted with a phenyl.
  • R 1 is C2alkyl each of R 2 and R 2 ’ are H.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this disclosure, unless only one of the isomers is specifically indicated. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers.
  • the compounds of the disclosure are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2- methylpropyl), and t-butyl (1,1 -dimethylethyl).
  • an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
  • Haloalkyl groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 -difluoroethyl, 2-fluoroethyl, 1 -chloro-2-fluoromethyl and 2-fluoroisobutyl
  • haloalkoxy refers to an alkoxy, or O-alkyl” group in which one or more of the hydrogen atoms are replaced by a halo group.
  • groups include but are not limited to, fluoromethoxy, chloromethoxy, bromomethoxy, fluoroethoxy, iodoethoxy and the like.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxyl group (OH).
  • OH hydroxyl group
  • groups include but are not limited to, hydroxymethyl, hydroxyethyl, and the like.
  • a “substituted” functional group is a functional, group having at least one hydrogen radical that is substituted with a non-hydrogen radical (i.e., a substituent).
  • a non-hydrogen radical i.e., a substituent
  • examples of non-hydrogen radicals include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkynyl, ether, aryl, heteroaryl, heterocycle, hydroxyl, oxy (or oxo), alkoxyl, ester, thioester, acyl, carboxyl, cyano, nitro, amino, sulfhydryl, and halo.
  • the substituents can be bound to the same carbon or different carbon atoms.
  • the term "pharmaceutically acceptable salt” refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefi t/risk ratio.
  • compositions described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.
  • acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.
  • acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.
  • Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, o
  • Basic addition salts include pharmaceutically acceptable metal and amine salts.
  • Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum.
  • the sodium and potassium salts are usually preferred.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Ammonia ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.
  • compositions that include an effective amount of compounds of the disclosure and one or more pharmaceutically acceptable excipients.
  • formulation is used interchangeable with “composition.”
  • an "effective amount” includes both a “therapeutically effective amount” and a “prophylactically effective amount.”
  • therapeutically effective amount refers to an amount effective in treating and/or ameliorating a disease or condition in a subject.
  • prolactically effective amount refers to an amount effective in preventing and/or substantially lessening the chances of a disease or condition in a subject.
  • patient and subject may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans).
  • the terms “patient” and “subject” include males and females.
  • excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • the compounds of the disclosure can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds can be administered all at once, as for example, by a bolus injection, multiple times, e.g. by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
  • the compounds disclosed herein and other pharmaceutically active compounds can be administered to a subject or patient by any suitable route, e.g. orally, topically, rectally, parenterally, (for example, subcutaneous injections, intravenous, intramuscular, intradermal, and intrathecal injection, or infusion techniques), or as a buccal, inhalation, or nasal spray.
  • the administration can be to provide a systemic effect (e.g. enteral or parenteral). All methods that can be used by those skilled in the art to administer a pharmaceutically active agent are contemplated.
  • the disclosed formulations can be administered orally or topically.
  • the compounds for use in the methods of the disclosure can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g. , about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • the compounds of the disclosure can be administered to a subject or patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient.
  • the specific dosage and dosage range that will be used can potentially depend on a number of factors, including the requirements of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular subject or patient is within the ordinary skill in the art
  • the compounds disclosed herein, and pharmaceutically acceptable salts thereof, can act as inhibitors of the attachment of SARS-CoV-2 viruses. Attachment of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2 (ACE2), cathepsin L, or TMPRSS2 in a subject To date there remains no FDA approved commercially available SARS-CoV-2 attachment inhibitors. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus attachment onto target cells.
  • ACE2 angiotensin-converting enzyme 2
  • TMPRSS2 TMPRSS2
  • the disclosure provides a method of inhibiting the angiotensin converting enzyme 2 (ACE2) receptor, cathepsin L, or transmembrane protease, serine 2 (TMPRSS2) activity comprising contacting the ACE2, cathepsin-L or TMPRSS2 with a compound according to Formula (I), (II), (III), or (IV).
  • ACE2 angiotensin converting enzyme 2
  • TMPRSS2 transmembrane protease
  • TMPRSS2 transmembrane protease
  • TMPRSS2 transmembrane protease
  • TMPRSS2 serine 2
  • the disclosure provides a method of preventing and/or treating a SARS-CoV-2 virus in a subject comprising contacting the SARS-CoV-2 with an effective amount of a compound or salt disclosed herein or a formulation thereof, in an amount effective to inhibit any one of ACE2, cathepsin L, and TMPRSS2.
  • the contacting occurs in vitro.
  • the contacting occurs in vivo.
  • the contacting comprises administering an effective amount of a compound or salt disclosed herein or a formulation thereof to a subject in need thereof.
  • the terms “patient” and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e , non-human animals) and humans Particular patients are mammals (e.g., humans). In various cases, the subject suffers from a disease or disorder associated with SARS-CoV-2
  • Compound 27 can be synthesized by published methods (Preparation of phenylaminopyrimidine derivatives and analogs as protein kinase inhibitors, WG2009032861 A1).
  • Compound 28 can be commercially obtained from Life Chemicals with catalog number F0526-1327.
  • Compound 29 can be synthesized by variations on published methods (X. Song, Y. He, M. Koenig, Y. Shin, R. Noel, W. Chen, Y-Y. Ling, D.
  • Compounds 36-37 were commercially obtained from Chembridge with catalog numbers 94256426 and 54863471.
  • Compound 38 can be commercially obtained from Life Chemicals with catalog number F1299-0404
  • Compound 39 can be commercially obtained from Sigma Aldrich with catalog number S-201 .
  • Compound 41 can be commercially obtained from ChemDiv with catalog number 8009-7916
  • Compounds 42, 45, and 47 can be synthesized by published methods (Bicyclic heteroaryls as kinase inhibitors and their preparation, WG2011050245 A1).
  • Compound 43 can be commercially obtained from Enamine with catalog number Z44611499, formerly T5255047).
  • Compound 44 can be commercially obtained from ChemDiv with catalog number Y508-3093.
  • Compound 46 can be commercially obtained from Enamine with catalog number Z56915465, formerly T0516-9493).
  • hACE-2-H1299 cells were seeded at 250 cells 12 piL/well into a 1536 well assay plate (Aurora 2110-11020-s). After addition of 10 nl of test compounds or vehicle into the appropriate well, plates were incubated 24 hours at 37°C and 5% CO2. Following the incubation, 2 piL / well of assay media (RPMI-1640 supplemented with 10 % FBS, 1X Antibiotic-Antimycotic and 1 pg/ml puromycin) was dispensed for column 1-3.
  • the hACE-2-H1299 cells were seeded at 250 cells / 2 piL / well for column 4-48 of the assay plates (Aurora 2110-11020-s). For columns 1-3, 2 piL/well of assay media were dispensed. After addition of 10 nl of compounds, plates were incubated 24 hours at 37°C and 5% CO2. Following that incubation, 2 piL / well of assay media to all wells was added. The plates were further incubated for 48 hours at 37°C and 5% CO2. The plates were then removed from that atmosphere and incubated at room temperature for 10 minutes followed by the addition of 4 pj L / well of CellTiter-Glo reagents (Promega G7573). After 10 minutes incubation at room temperature, luminescence was measured using Pherastar (BGM).
  • compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise.
  • methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise.
  • the invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.

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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés qui agissent en tant qu'inhibiteurs contre la fixation du virus SARS-CoV-2, des formulations pharmaceutiques de ceux-ci, et des méthodes d'utilisation desdits composés pour prévenir et traiter des maladies associées au virus SARS-CoV-2.
PCT/US2025/014432 2024-02-09 2025-02-04 Inhibiteurs de fixation du sars-cov-2 et leur utilisation thérapeutique Pending WO2025170898A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110065703A1 (en) * 2007-03-12 2011-03-17 Jay Jie-Qiang Wu Novel agents of calcium ion channel modulators
JP2013035778A (ja) * 2011-08-08 2013-02-21 Kowa Co ベンジルアミン誘導体を有効成分とするｔｌｒ９阻害剤
WO2023194840A1 (fr) * 2022-04-05 2023-10-12 Unichem Laboratories Limited Composés tricycliques substitués et leur utilisation dans la covid-19
US20240018126A1 (en) * 2022-07-06 2024-01-18 Aligos Therapeutics, Inc. Anti-viral compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110065703A1 (en) * 2007-03-12 2011-03-17 Jay Jie-Qiang Wu Novel agents of calcium ion channel modulators
JP2013035778A (ja) * 2011-08-08 2013-02-21 Kowa Co ベンジルアミン誘導体を有効成分とするｔｌｒ９阻害剤
WO2023194840A1 (fr) * 2022-04-05 2023-10-12 Unichem Laboratories Limited Composés tricycliques substitués et leur utilisation dans la covid-19
US20240018126A1 (en) * 2022-07-06 2024-01-18 Aligos Therapeutics, Inc. Anti-viral compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG ET AL.: "Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus", PHYTOMEDICINE, vol. 79, 2 September 2020 (2020-09-02), pages 1 - 8, XP086303256, DOI: 10.1016/j.phymed.2020.153333 *

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