WO2020216906A1 - Composés pour le traitement d'une maladie de stockage du glycogène - Google Patents

Composés pour le traitement d'une maladie de stockage du glycogène Download PDF

Info

Publication number
WO2020216906A1
WO2020216906A1 PCT/EP2020/061469 EP2020061469W WO2020216906A1 WO 2020216906 A1 WO2020216906 A1 WO 2020216906A1 EP 2020061469 W EP2020061469 W EP 2020061469W WO 2020216906 A1 WO2020216906 A1 WO 2020216906A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
belinostat
histone deacetylase
compound
Prior art date
Application number
PCT/EP2020/061469
Other languages
English (en)
Inventor
Tomàs PINÓS FIGUERAS
Noemi DE LUNA SALVA
Eduardo GALLARDO VIGO
Ramon MARTÍ SEVES
Original Assignee
Consorcio Centro de Investigación Biomédica en Red, M.P.
Fundació Institut De Recerca De L'hospital De La Santa Creu I Sant Pau
Fundació Hospital Universitari Vall D'hebron - Institut De Recerca
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Consorcio Centro de Investigación Biomédica en Red, M.P., Fundació Institut De Recerca De L'hospital De La Santa Creu I Sant Pau, Fundació Hospital Universitari Vall D'hebron - Institut De Recerca filed Critical Consorcio Centro de Investigación Biomédica en Red, M.P.
Publication of WO2020216906A1 publication Critical patent/WO2020216906A1/fr

Links

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

Definitions

  • the present invention refers to a novel therapy for a glycogen storage disease.
  • Glycogen is a branched polymer of up to 55.000 glucose residues.
  • the source of the glucose residues that forms glycogen is the ingested food.
  • the glycogen degradation takes place in the cytoplasm by glycogen phosphorylase and inside the lysosomes by a- glucosidase.
  • Three isoforms of glycogen phosphorylase have been described, the expression of said isoforms being tissue specific.
  • the brain isoform (GP-BB) encoded by PYGB, is expressed mainly in fetal tissues and in adult tissues which is confined to brain and heart.
  • the liver isoform (GP-LL) is encoded by PYGL and expressed in the liver.
  • the muscle isoform (GP-MM) encoded by PYGM is expressed in skeletal muscle.
  • the PYGM deficiency caused by mutations in the gene, affects all skeletal muscles and causes McArdle, disease also termed glycogen storage disease type V (OMIM® n° 232600). Muscle biopsies from McArdle patients show abnormal storage of muscle glycogen and a deficiency in GP-MM staining.
  • McArdle disease also called a glycogen storage disease type V
  • McArdle disease are unable to mobilize ATP from glycogen degradation when doing exercise, leading a crisis together with discomfort signs, pain, fatigue and even myoglobinuria and rhabdomyolysis.
  • the disease has a broad clinical heterogeneity, but there are some clinical features that are common to the majority of patients. During exercise, patients should stop the activity allowing the symptoms to disappear.
  • glycogen storage diseases such as Pompe’s disease (also called a glycogen storage disease type II), are likewise without effective pharmacological therapy. New effective strategies for treating glycogen storage diseases are therefore desirable.
  • the inventors have found that the compounds belinostat and mocetinostat significantly reduce glycogen accumulation in myogenic precursor cells (mpcs) of knock-in (Kl)
  • McArdle mice carrying the mutation p.R50X in homozygosis are a good“in vitro” model of McArdle disease because they mimic the glycogen accumulation that is commonly found in the skeletal muscle from individuals with McArdle disease (Nogales- Gadea et al, Brain 2012).
  • Belinostat and mocetinostat belong to the family of histone deacetylase inhibitor enzymes, a class of enzymes implicated in the remodelling of chromatin and in the epigenetic regulation of gene expression.
  • the present inventors have surprisingly found that these compounds allow the transcription of PYGB and/or PYGL genes in mature skeletal muscle, thus increasing the amount of brain and liver isoforms of glycogen phosphorylase in the muscle cells, resulting in effective reduction of glycogen in said cells.
  • the increase in expression of PYGB and/or PYGL as well as consequent glycogen reduction in mpcs of Kl McArdle mice is shown in figures 1-6. Accordingly, belinostat and mocetinostat can be used for the treatment and/or prevention of McArdle disease.
  • the present application thus refers to a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention and/or prevention of McArdle disease.
  • This aspect may be reformulated as use of a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and/or prevention of McArdle disease.
  • the application also relates to a method for treating and/or preventing McArdle disease that comprises administering a therapeutically effective amount of a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, together with
  • inhibitor refers to an agent or compound that is able to block, partially block, interfere, decrease, suppress, reduce or deactivate a target protein (i.e. a histone deacetylase).
  • the term“treatment” or variants of the word means to reduce, stabilize, or inhibit the progression of McArdle disease in patients already suffering from the disease.
  • the term“prevention” is used herein to refer to include both preventing the onset of clinically evident McArdle disease altogether and delaying its onset.
  • Belinostat (PXD 101), lUPAC name (E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2- enamide, is a low-molecular-weight hydroxamic acid histone deacetylase inhibitor of formula I and CAS registry number 414864-00-9. This compound is commercially available under the trade name Beleodaq ® .
  • Mocetinostat (MGCD0103), lUPAC name N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin- 2-yl)amino]methyl]benzamide, is a small molecule histone deacetylase inhibitor, highly specific for classes I and IV histone deacetylases. Mocetinostat’s chemical formula is shown as formula II below. Its CAS registry number is 726169-73-9.
  • Compound PFI-1 lUPAC name 2-methoxy-N-(3-methyl-2-oxo-1 ,4-dihydroquinazolin-6- yl)benzenesulfonamide, is a potent and highly selective digydroquinazoline-2-one inhibitor.
  • PFI-1 chemical formula is shown as formula III below. Its CAS registry number is 1403764-72-6.
  • Compound PFI-1 efficiently blocks the interaction of BET bromodomains proteins with acetylated histone tails having antiproliferative effects in leukaemic cell lines and efficiently abrogating their clonogenic growth.
  • the present application also relates to a compound PFI-1 , or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of McArdle disease.
  • This may be reformulated as use of compound PFI-1 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and/or prevention of McArdle disease.
  • the application also relates to a method for treating and/or preventing McArdle disease that comprises administering a therapeutically effective amount of compound PFI-1 , or a pharmaceutically acceptable salt thereof, together with
  • salts of the compounds of the invention there is no limitation on the type of salt of the compounds of the invention that can be used, provided that these are pharmaceutically or veterinary acceptable when they are used for therapeutic purposes.
  • pharmaceutically or veterinary acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • preparation of pharmaceutically or veterinary acceptable salts of the compounds of the invention can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically or veterinary acceptable base or acid in water or in an organic solvent or in a mixture of them.
  • the compounds of the invention and their respective salts may differ in some physical properties but they are equivalent for the purposes of the present invention.
  • the compounds of the invention may be in crystalline form either as free solvation compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art.
  • the solvated forms with pharmaceutically, cosmetically or veterinary acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for the purposes of the invention.
  • stereoisomer refers to all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • the present invention relates to each of these
  • Diastereoisomers and enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediates or on compounds of the invention.
  • Optically pure isomers can also be individually obtained using enantiospecific synthesis.
  • metabolites and derivatives of belinostat, mocetinostat and PFI-1 are also contemplated in the present invention since they have the same effect regarding expression of brain and/or liver isoforms of glycogen phosphorylase in skeletal muscle and/or reduction of glycogen accumulation in the skeletal muscle, thus being effective for treating or preventing McArdle disease.
  • derivatives and metabolites of belinostat are disclosed by the FDA in its pharmacology review on belinostat (beleodac) (application number: 2062560rig1s000): belinostat glucoronide (M18, TP201806, PubChem ref.
  • Methylated belinostat PX106507, PubChem ref. 72376230
  • belinostat amide M21 , PX118624, PubChem ref. 69620795
  • 3-ASBA M24, 3-(AnilinoSulfonyl)Benzene Carboxylic Acid, TP201859, PubChem ref. 759339
  • belinostat acid M26, PXD101-6, PX118623, (2E)-3-[3- (Phenylsulfamoyl)phenyl]acrylic acid).
  • the compound for use in treating and/or preventing McArdle disease is belinostat. In another embodiment, the compound for use in treating and/or preventing McArdle disease is mocetinostat.
  • the dose of histone deacetylase inhibitor for use in treating and/or preventing McArdle disease is from 1 to 3000 mg/m 2 /d, or from 10 to 2000 mg/m 2 /d expressed as histone deacetylase inhibitor in free form.
  • the dose of histone deacetylase inhibitor for use in treating and/or preventing McArdle disease is from 15 to 3000 mg/m 2 /d for belinostat, or a pharmaceutically acceptable salt thereof expressed as belinostat free form.
  • the dose of mocetinostat, or a pharmaceutically acceptable salt thereof is from 15 to 2000 mg/m 2 /d, or from 50 to 1500 mg/m 2 /d, or from 100 to 2000 mg/m 2 /d or from 500 to 1500 mg/m 2 /d or from 800 to 1300 mg/m 2 /d, for example around 1000 mg/m 2 /d.
  • the dose of mocetinostat, or a pharmaceutically acceptable salt thereof is from 1 to 500 mg/m 2 /d.
  • the dose of mocetinostat may be from 12.5 to 56 mg/m 2 /d or from 85 to 110 mg/m 2 /d or from 10 to 200 mg/m 2 /d, or from 12.5 to 110 mg/m 2 /d.
  • the dose is form 0.1 to 10000 mg/m 2 /d, or from 1 to 3000 mg/m 2 /d, or from 100 to 5000 mg/m 2 /d, or from 200 to 2000 mg/m 2 /d.
  • the doses or therapeutically effective amounts of the pharmaceutically acceptable salts of the compounds of the invention are expressed as the corresponding compound in free form, even if not explicitly mentioned.
  • belinostat, mocetinostat and PFI-1 are active pharmaceutical ingredients that, although currently approved or in clinical trials for anti-cancer treatment, are associated to a certain degree of dose dependent toxicity, which conditions their use. Combination of these active ingredients for the treatment and/or prevention of McArdle disease thus provides a further advantage by greatly reducing the amount of therapeutically effective active ingredients required and consequently their associated toxicity.
  • a greater glycogen reduction is achieved by combining belinostat or mocetinostat with compound PFI-1 , while, at the same time the effective concentration of the compounds is reduced.
  • the synergistic effect achieved by combining belinostat or mocetinostat with compound PFI-1 has been shown over a wide range of concentrations and is relevant both in the increase of expression of glycogen phosphorylase in the muscle cells as well as in reduction of glycogen.
  • the term “synergy” or“synergistic” is used herein to mean an effect greater than the sum of the effects obtained independently with each one of the components of the drug combination.
  • Synergy may be determined by methods known to the skilled in the art.
  • the present application also refers to a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of McArdle disease, wherein the histone deacetylase inhibitor is for use in combination with compound PFI-1 , or a pharmaceutically acceptable salt thereof.
  • histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of McArdle disease wherein the histone deacetylase inhibitor is for use in combination with compound PFI-1.
  • the application refers to compound PFI-1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of McArdle disease, wherein the compound PFI-1 is for use in combination with a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof.
  • a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof
  • mocetinostat or a pharmaceutically acceptable salt thereof.
  • the histone deacetylase inhibitor for use in any of the combination therapies disclosed above is belinostat, or a pharmaceutically acceptable salt thereof.
  • the histone deacetylase inhibitor for use in any of the combination therapies disclosed above is mocetinostat, or a pharmaceutically acceptable salt thereof.
  • the present application also envisages combining all three active ingredients: belinostat, or a pharmaceutically acceptable salt thereof, mocetinostat, or a pharmaceutically acceptable salt thereof, and PFI-1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of McArdle disease.
  • the active ingredients for use in treating and/or preventing McArdle disease in any of the combination therapies described above may be combined by administering them together or separately, in any order, within a therapeutically effective interval.
  • the dose of belinostat, mocetinostat and FPI-1 can be reduced with respect to the dose required when used individually.
  • the dose of belinostat, or a pharmaceutically acceptable salt thereof, when used in combination as defined above may be from 0.1 to 500 mg/m 2 /day, or from 1 to 200 mg/m 2 /day, or from 1 to 100 mg/m 2 /day, or from 10 to 200 mg/m 2 /day, or from 50 to 150 mg/m 2 /day.
  • mocetinostat may be for example from 0.1 to 100 mg/m 2 /day, or from 1 to 100 mg/m 2 /day, or from 1 to 20 mg/m 2 /day or from 1 to 10 mg/m 2 /day.
  • the dose of PFI-1 may be from 0.1 to 1000 mg/m 2 /day, or from 0.1 to 100 mg/m 2 /day or from 0.01 to 1000 mg/m 2 /day, or from 0.01 to 100 mg/m 2 /day or from 1 to 100 mg/m 2 /day.
  • Another aspect of the invention refers to a combination comprising: a) a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, and b) compound FPI-1 , or a pharmaceutically acceptable salt thereof.
  • the histone deacetylase inhibitor in the combination is belinostat, or a pharmaceutically acceptable salt thereof.
  • the histone deacetylase inhibitor in the combination is mocetinostat, or a pharmaceutically acceptable salt thereof.
  • the molar ratio of histone deacetylase inhibitor to compound FPI-1 , or a pharmaceutically acceptable salt thereof may be from 1 :1 to 1 :100.
  • the molar ratio of histone deacetylase inhibitor to compound FPI-1 may be from 1 :2 to 1 :50.
  • the ratio of belinostat to compound FPI-1 is from 1 :2 to 1 :50, or from 1 :5 to 1 :30, or from 1 :2 to 1 :10, or from 1 :2 to 1 :30, or from 1 :10 to 1 :30.
  • the ratio of mocetinostat to compound FPI-1 is from 1 :20 to 1 :40, or from 1 :20 to 1 :30 or from 1 :30 to 1 :40.
  • compositions may be prepared comprising a therapeutically effective amount of belinostat, mocetinostat or compound PFI-1 , or pharmaceutically acceptable salts therefrom, together with pharmaceutically acceptable excipients and/or carriers.
  • therapeutically effective amount refers to the amount of PRR agonist that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • pharmaceutically acceptable excipients or carriers refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • compositions of the invention as defined above are for use in the treatment and/or prevention of McArdle disease.
  • McArdle disease for example the application
  • a pharmaceutical composition comprising a therapeutically effective amount of a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of McArdle disease.
  • the application also envisages a pharmaceutical composition comprising a therapeutically effective amount of compound PFI-1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of McArdle disease.
  • the therapeutically effective amount of histone deacetylase inhibitor in the pharmaceutical composition may be from 1 to 3000 mg/m 2 /d, or from 10 to 2000 mg/m 2 /d expressed as histone deacetylase inhibitor in free form.
  • the therapeutically effective amount of belinostat, or a pharmaceutically acceptable salt thereof may be from 15 to 3000 mg/m 2 /d, or from 15 to 2000 mg/m 2 /d, or from 50 to 1500 mg/m 2 /d, or from 100 to 2000 mg/m 2 /d or from 500 to 1500 mg/m 2 /d or from 800 to 1300 mg/m 2 /d, for example around 1000 mg/m 2 /d.
  • the therapeutically effective amount of mocetinostat, or a pharmaceutically acceptable salt thereof may be from 1 to 500 mg/m 2 /d.
  • the dose of mocetinostat may be from 12.5 to 56 mg/m 2 /d or from 85 to 110 mg/m 2 /d or from 10 to 200 mg/m 2 /d, or from 12.5 to 110 mg/m 2 /d.
  • the therapeutically effective amount in the pharmaceutical composition of FPI-1 , or a pharmaceutically acceptable salt thereof may be from 0.1 to 10000 mg/m 2 /d, or from 1 to 3000 mg/m 2 /d, or from 100 to 5000 mg/m 2 /d, or from 200 to 2000 mg/m 2 /d.
  • a pharmaceutical composition comprising a therapeutically effective amount of a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, and compound PFI-1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers.
  • a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, and compound PFI-1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers.
  • the therapeutically effective amounts of histone deacetylase inhibitor and PFI-1 may be reduced when used in combination in a composition of the invention as compared to the compounds used individually.
  • the compounds used individually for example, in such compositions, the
  • therapeutically effective amount of belinostat, or a pharmaceutically acceptable salt thereof may be from 0.1 to 500 mg/m 2 /day, or from 1 to 200 mg/m 2 /day, or from 1 to 100 mg/m 2 /day, or from 10 to 200 mg/m 2 /day, or from 50 to 150 mg/m 2 /day and the
  • therapeutically effective amount of FPI-1 may be from 0.1 to 1000 mg/m 2 /day, or from 0.1 to 100 mg/m 2 /day or from 0.01 to 1000 mg/m 2 /day, or from 0.01 to 100 mg/m 2 /day or from 1 to 100 mg/m 2 /day.
  • the therapeutically effective amount of mocetinostat, or a pharmaceutically acceptable salt thereof may be from 0.1 to 100 mg/m 2 /day, or from 1 to 100 mg/m 2 /day, or from 1 to 20 mg/m 2 /day, or from 1 to 10 mg/m 2 /day and the therapeutically effective amount of FPI-1 , or a pharmaceutically acceptable salt thereof, may be from 0.1 to 1000 mg/m 2 /day, or from 0.1 to 100 mg/m 2 /day or from 0.01 to 1000 mg/m 2 /day, or from 0.01 to 100 mg/m 2 /day or from 1 to 100 mg/m 2 /day.
  • a pharmaceutical composition comprising a therapeutically effective amount of belinostat, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of mocetinostat, or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amounts of belinostat and mocetinostat may be as disclosed for the pharmaceutical compositions disclosed above.
  • the election of the pharmaceutical formulation will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral and topical administration.
  • the pharmaceutical composition may be formulated for oral administration and may contain one or more physiologically compatible carriers or excipients, in solid or liquid form. These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the administration route for mocetinostat is oral.
  • the pharmaceutical composition may be formulated for parenteral administration in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical or veterinary excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such compositions.
  • These pharmaceutical or veterinary compositions may be injected intramuscularly,
  • the administration route for belinostat is parenteral, in particular, intravenous.
  • the pharmaceutical composition may also be formulated for topical administration.
  • Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
  • compositions may be in any form, including, among others, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
  • excipients and/or carriers can readily be determined by those skilled in the art according to the type of formulation being prepared.
  • One further aspect of the invention provides a combination comprising a) a histone deacetylase inhibitor selected from belinostat, mocetinostat and a pharmaceutically acceptable salt of any of these compounds, and b) compound FPI-1 , or a
  • the treatment and/or prevention comprises administering to a subject simultaneously, sequentially or separately a pharmaceutical composition comprising a therapeutically effective amount of the histone deacetylase inhibitor together with pharmaceutically acceptable excipients and/or carriers and a pharmaceutical composition comprising a therapeutically effective amount of the compound PFI-1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers.
  • the therapeutically effective amounts of histone deacetylase inhibitor and PFI-1 may be reduced when used in combination as compared to the compounds used individually. Examples of therapeutically effective amounts of histone deacetylase inhibitors and PFI-1 when used in combination have been disclosed above.
  • the application also provides in another aspect a combination comprising: a) a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, and b) compound FPI-1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of McArdle disease, wherein the treatment and/or prevention comprises administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of the histone deacetylase inhibitor and of the compound PFI-1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers.
  • the therapeutically effective amounts of histone deacetylase inhibitor and PFI-1 may be reduced when used in combination as compared to the compounds used individually. Examples of therapeutically effective amounts of histone deacetylase inhibitors and PFI-1 when used in combination have been disclosed above.
  • kits may also be formulated in a kit.
  • kit or package contains the active ingredients of interest, in this case, a histone deacetylase inhibitor selected from belinostat and mocetinostat and compound PFI-1 , together with instructions to be administered in combination therapy with each other for treating and/or preventing McArdle disease.
  • active ingredients of interest in this case, a histone deacetylase inhibitor selected from belinostat and mocetinostat and compound PFI-1 , together with instructions to be administered in combination therapy with each other for treating and/or preventing McArdle disease.
  • a package or kit of parts comprising a) a first pharmaceutical composition which comprises a therapeutically effective amount of a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers; and b) a second pharmaceutical composition which comprises a therapeutically effective amount of compound FPI-1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers.
  • a first pharmaceutical composition which comprises a therapeutically effective amount of a histone deacetylase inhibitor selected from belinostat, or a pharmaceutically acceptable salt thereof, and mocetinostat, or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers
  • a second pharmaceutical composition which comprises a therapeutically effective amount of compound FPI-1 , or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients and/or carriers.
  • kit of parts or package also contains instructions for the first and second pharmaceutical compositions to be administered in combination therapy with each other for treating and/or preventing McArdle disease.
  • the present disclosure also contemplates all the compounds, combinations and compositions as disclosed herein for use in the prevention and/or treatment of a metabolic disorder caused by enzyme deficiency, in particular glycogen storage diseases such as, Pompe’s disease, Hers’ disease and Type IX glycogen storage disease.
  • a metabolic disorder caused by enzyme deficiency in particular glycogen storage diseases such as, Pompe’s disease, Hers’ disease and Type IX glycogen storage disease.
  • All the embodiments and examples (such as disclosed doses, therapeutically effective amounts, combinations, compositions and kits) disclosed above for the prevention and/or treatment of McArdle disease are applicable to the prevention and/or treatment of a metabolic disorder caused by enzyme deficiency, in particular glycogen storage diseases, such as those enumerated above.
  • Figure 1 shows glycogen accumulation as observed by PAS staining in myogenic precursor cells (mpcs) of knock-in (Kl) McArdle mice carrying the mutation p.R50X in homozygosis treated with different concentrations belinostat (Bel), mocetinostat (Moc) and PFI-1.
  • Bel belinostat
  • Moc mocetinostat
  • PFI-1 PFI-1
  • Figure 2 shows Pgym, Pygb, Pygl , Gys1 expression levels as determined by reverse transcription real time quantitative PCR in mpcs treated with the indicated concentrations of belinostat (Bel), mocetinostat (Moc), PFI-1 , danusertib (Dan) and JNJ15.
  • Figure 2A shows the levels of expression of Pgym and Pygb.
  • Figure 2B shows the levels of expression of Pygl and Gys1.
  • Ctrl is control sample of untreated cells.
  • Figure 3 shows Pygb expression as determined by western blot in mpcs treated with the indicated concentrations of belinostat (Bel), mocetinostat (Moc) and PFI-1.
  • Bel belinostat
  • Moc mocetinostat
  • PFI-1 PFI-1
  • Figure 4 shows glycogen accumulation as observed by PAS staining in mpcs treated with different concentrations of belinostat (Bel) in combination with different concentrations of PFI-1.
  • Figure 5 shows glycogen accumulation as observed by PAS staining in mpcs treated with different concentrations of mocetinostat (Moc) in combination with different concentrations of PFI-1.
  • Figure 6 shows Pgym, Pygb, Pygl and Gys1 expression levels as determined by reverse transcription real time quantitative PCR in mpcs treated with the indicated concentrations of belinostat (Bel) or mocetinostat (Moc) in combination with different concentrations of PFI-1.
  • Figure 6A shows the levels of expression of Pgym and Pygb.
  • Figure 6B shows the levels of expression of Pygl and Gys1.
  • Ctrl is control sample of untreated cells.
  • Figure 7 shows glycogen accumulation as observed by PAS staining in mpcs from Pompe mice (Gaa tm1Rabn ) treated with different concentrations of Belinostat, mocetinostat and PFI- 1.
  • Ctrl is control sample of Pompe untreated cells.
  • Myogenic precursor cells were isolated from 8-week-old knock-in (Kl) McArdle mice carrying the mutation p.R50X in homozygosis (Nogales-Gadea et al, Brain 2012). Briefly, all muscles from lower limbs were digested with 0.2% Pronase (Calbiochem, Darmstadt, Germany). After pre-plating step in non-coated dishes to allow fibroblasts to adhere, supernatant containing mpcs were added to 2% gelatin-coated dishes.
  • the proliferation media was composed of: HAM-F10 media (Lonza Group Ltd, Basel,
  • differentiation media containing Dulbbeco’s modified Eagle’s medium supplemented with 2% of non-inactivated horse serum, 2mM glutamine, 100 mg/ml penicillin, 100 mg/ml streptomycin and 0.25 mg/ml amphotericin B.
  • Treated and non-treated muscle cultures were incubated with 0.5% of PAS (Sigma- Aldrich, Madrid, Spain) in distilled water. Cells were washed with distilled water and then incubated with Schiff solution (Merck, Darmstad, Germany) for 15 min. Quantification of PAS staining was performed using Fiji software (Schindelin, J.; et al., Nature methods, 2019).
  • RNA from treated and non-treated cell cultures was extracted using Trizol (Life Technologies, Carlsbad, CA, USA). 0.5 mg of total RNA was DNAse-treated (Life Technologies, Carlsbad, CA, USA).
  • Treated and non-treated cells were homogenized with a lysis buffer containing 40mM glycophosphate, 40mM NaF, 10mM EDTA and 20mM of b-mercaptoethanol.
  • the samples were placed in boiling for 3 min and centrifuged at 9500xg for 3min, before 100mg of protein were loaded in each lane. Unspecific binding sites on the blots were blocked by incubation with 5% low-fat dried milk powder in a PBS. Thereafter, rabbit policlonal anti- PYGB antibody (Abeam, Cambridge, UK), goat anti-PYGM antibody (kindly provided by Dr. Martinuzzi, Instituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea, Treviso, Italy), rabbit anti-glycogen synthase antibody (Cell Signaling Technology,
  • PYGB protein expression was also tested by western blot in the same treated cultures, confirming the increase of protein expression in cultures treated with belinostat and mocetinostat, but not PFI-1 ( Figure 3). It was therefore hypothesized that glycogen reduction in Kl muscle cultures is mediated by Pgyb and Pgyl expression in these cells in the case of belinostat and mocetinostat, but not for PFI-1. It is known that patients with a rare splice site mutation resulting in a small amount of residual enzyme (1-2.5%) have a milder phenotype that is only evident on exercise testing (Vissing J, et al, Brain 2009). This finding indicates that very low levels of enzyme would be sufficient to ameliorate symptoms in McArdle patients, so a lower to moderate increase in GP isoforms expression with the consequent reduction of glycogen in muscle, would be beneficial for the patients.
  • PFI-1 seems to reduce glycogen accumulation by reducing glycogen synthase expression.
  • Myogenic precursor cells were isolated from 8-week-old knock-out (KO) Pompe mice (Gaa tm1Rabn ). Briefly, all muscles from lower limbs were digested with 0.2% Pronase (Calbiochem, Darmstadt, Germany). After pre-plating step in non-coated dishes to allow fibroblasts to adhere, supernatant containing mpcs were added to 2% gelatin-coated dishes.
  • the proliferation media was composed of: HAM-F10 media (Lonza Group Ltd, Basel, Switzerland) supplemented with 20% FBS, 2mM glutamine, 1 % of sodium pyruvate, 1X non-essential aminoacids, 100 mg/ml penicillin, 100 mg/ml streptomycin and 0.25 mg/ml amphotericin B.
  • differentiation media containing Dulbbeco’s modified Eagle’s medium supplemented with 2% of non-inactivated horse serum, 2mM glutamine, 100 mg/ml penicillin, 100 mg/ml streptomycin and 0.25 mg/ml amphotericin B.
  • Treated and non-treated muscle cultures were incubated with 0.5% of PAS (Sigma- Aldrich, Madrid, Spain) in distilled water. Cells were washed with distilled water and then incubated with Schiff solution (Merck, Darmstad, Germany) for 15 min. Quantification of PAS staining was performed using Fiji software (Schindelin, J.; et al., Nature methods, 2019).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur d'histone désacétylase choisi parmi le belinostat, ou un sel pharmaceutiquement acceptable de celui-ci, et du mocétinostat, ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans le traitement et/ou la prévention d'une maladie de stockage du glycogène. L'invention concerne également des compositions pharmaceutiques comprenant lesdits inhibiteurs d'histone désacétylase ainsi que des combinaisons synergiques des Inhibiteurs d'histone désacétylase avec le composé PFI -1.
PCT/EP2020/061469 2019-04-26 2020-04-24 Composés pour le traitement d'une maladie de stockage du glycogène WO2020216906A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19382320.0 2019-04-26
EP19382320 2019-04-26

Publications (1)

Publication Number Publication Date
WO2020216906A1 true WO2020216906A1 (fr) 2020-10-29

Family

ID=66334337

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/061469 WO2020216906A1 (fr) 2019-04-26 2020-04-24 Composés pour le traitement d'une maladie de stockage du glycogène

Country Status (1)

Country Link
WO (1) WO2020216906A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012162535A1 (fr) * 2011-05-24 2012-11-29 Lixte Biotechnology, Inc. Utilisation d'inhibiteurs de phosphatase ou d'inhibiteurs d'histone désacétylase pour traiter des maladies caractérisées par la perte d'une fonction protéique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012162535A1 (fr) * 2011-05-24 2012-11-29 Lixte Biotechnology, Inc. Utilisation d'inhibiteurs de phosphatase ou d'inhibiteurs d'histone désacétylase pour traiter des maladies caractérisées par la perte d'une fonction protéique

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
DOUILLARD-GUILLOUX ET AL., BIOCHEM BIOPHYS RES COMMUN., 2009
DOUILLARD-GUILLOUX GMOULY VCAILLAUD CRICHARD E: "Immortalization of murine muscle cells from lysosomal a-glucosidase deficient mice: A new tool to study pathophysiology and assess therapeutic strategies for Pompe disease", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 388, no. 2, 2009, pages 333 - 338, XP026522078, DOI: 10.1016/j.bbrc.2009.08.006
FDA PHARMACOLOGY REVIEW ON BELINOSTAT (BELEODAC
GIMSING PETER: "Belinostat: a new broad acting antineoplastic histone deacetylase inhibitor", EXPERT OPINION ON INVESTIGATIONAL DRUGS, INFORMA HEALTHCARE, UK, vol. 18, no. 4, 1 April 2009 (2009-04-01), pages 501 - 508, XP002531594, ISSN: 1354-3784, DOI: 10.1517/13543780902852560 *
J.MCC. HOWELL ET AL: "Investigating sodium valproate as a treatment for McArdle disease in sheep", NEUROMUSCULAR DISORDERS, vol. 25, no. 2, 1 February 2015 (2015-02-01), GB, pages 111 - 119, XP055629977, ISSN: 0960-8966, DOI: 10.1016/j.nmd.2014.10.002 *
MONTSERRAT PÉREZ-SALVIA ET AL: "Bromodomain inhibitors and cancer therapy: From structures to applications", EPIGENETICS, vol. 12, no. 5, 2 December 2016 (2016-12-02), US, pages 323 - 339, XP055452716, ISSN: 1559-2294, DOI: 10.1080/15592294.2016.1265710 *
N. DE LUNA ET AL: "Sodium valproate increases the brain isoform of glycogen phosphorylase: looking for a compensation mechanism in McArdle disease using a mouse primary skeletal-muscle culture in vitro", DISEASE MODELS & MECHANISMS, vol. 8, no. 5, 11 March 2015 (2015-03-11), GB, pages 467 - 472, XP055629932, ISSN: 1754-8403, DOI: 10.1242/dmm.020230 *
NOGALES-GADEA GPINOS TLUCIA AARENAS JCAMARA YBRULL ADE LUNA NMARTIN MAGARCIA-ARUMI EMARTI R: "Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease", BRAIN, vol. 135, 2012, pages 2048 - 57, XP055629645, DOI: 10.1093/brain/aws141
S. PICAUD ET AL: "PFI-1, a Highly Selective Protein Interaction Inhibitor, Targeting BET Bromodomains", CANCER RESEARCH, vol. 73, no. 11, 1 June 2013 (2013-06-01), pages 3336 - 3346, XP055130754, ISSN: 0008-5472, DOI: 10.1158/0008-5472.CAN-12-3292 *
SCHINDELIN, J. ET AL., NATURE METHODS, 2019
SCHINDELIN, J.ARGANDA-CARRERAS, I.FRISE, E. ET AL.: "Fiji: an open-source platform for biological-image analysis", NATURE METHODS, vol. 9, no. 7, 2012, pages 676 - 682, XP055343835, DOI: 10.1038/nmeth.2019
VISSING JDUNO MSCHWARTZ MHALLER RG: "Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease", BRAIN, vol. 132, 2009, pages 1545 - 52
YANIS BOUMBER ET AL: "Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor", EXPERT OPINION ON INVESTIGATIONAL DRUGS, vol. 20, no. 6, 10 May 2011 (2011-05-10), UK, pages 823 - 829, XP055632336, ISSN: 1354-3784, DOI: 10.1517/13543784.2011.577737 *

Similar Documents

Publication Publication Date Title
CN110087647B (zh) 氨基酸组合物及肝疾病的治疗方法
KR102014883B1 (ko) 근위축성 측삭 경화증 치료용 신규 조성물
Bogetofte et al. Levodopa therapy for Parkinson's disease: history, current status and perspectives
US6306910B1 (en) Use of Gaba-analogues for treating insomnia
Bjelaković et al. Metabolic correlations of glucocorticoids and polyamines in inflammation and apoptosis
CA2766282C (fr) Inhibiteurs de la carnitine palmitoyltransferase-1 pour le traitement et la prevention de troubles provoques par une delipidation du tissu nerveux
EP3563841A1 (fr) Nouvelles approches therapeutiques pour le traitement de la maladie de parkinson
Dolci et al. Therapeutic induction of energy metabolism reduces neural tissue damage and increases microglia activation in severe spinal cord injury
BR112017022857B1 (pt) Composto, método para preparar o composto, uso de uma composição
CN109803647A (zh) α-丁酮酸、α-酮戊二酸和2-羟基丁酸用于刺激毛发生长
KR20210139293A (ko) 폐동맥 고혈압 및 연관 폐동맥 고혈압 치료방법 및 매일 투여
KR20110118830A (ko) Ｎｋ 수용체 길항제의 용도
EP3810272A1 (fr) Compositions et procédés pour la réduction ou le traitement de la fibrose
US20220193075A1 (en) Therapeutic drug for dyskinesia
JP2016128437A (ja) Ｈｄａｃ阻害剤と血小板減少症薬との組合せ
TW201618760A (zh) 使用半胱胺組合物治療亨廷頓氏病之方法
WO2020216906A1 (fr) Composés pour le traitement d'une maladie de stockage du glycogène
KR20050090443A (ko) 랑게르한스섬 세포 수를 증가시킴으로써 당뇨병을 치료하는키뉴레닌-３-하이드록실라제 저해제
US7915262B2 (en) Combination preparations comprising SLV308 and a dopamine agonist
EP3909568B1 (fr) Médicament pour la prévention ou le traitement de maladies neurodégératives
TW201406740A (zh) 用於抑制運動神經元自體吞噬之醫藥組合物及其應用
JP7142085B2 (ja) Ａｓｍｔ発現促進剤
US20210085676A1 (en) Treatment for age- and oxidative stress-associated muscle atrophy and weakness
WO2020084113A1 (fr) Sildénafil destiné à être utilisé dans le traitement de l'ostéoarthrite chez le cheval
EP3335730A1 (fr) Composés pour le traitement d'une adrénoleucodystrophie à liaison x

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20721564

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20721564

Country of ref document: EP

Kind code of ref document: A1