EP1746982A2 - Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis and cardiovascular diseases - Google Patents

Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis and cardiovascular diseases

Info

Publication number
EP1746982A2
EP1746982A2 EP05742909A EP05742909A EP1746982A2 EP 1746982 A2 EP1746982 A2 EP 1746982A2 EP 05742909 A EP05742909 A EP 05742909A EP 05742909 A EP05742909 A EP 05742909A EP 1746982 A2 EP1746982 A2 EP 1746982A2
Authority
EP
European Patent Office
Prior art keywords
linear
branched
alkyl
inhibitors
use according
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05742909A
Other languages
German (de)
English (en)
French (fr)
Inventor
Maurizio Crestani
Cristina Godio
Nico Mitro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universita degli Studi di Milano
Original Assignee
Universita degli Studi di Milano
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 Universita degli Studi di Milano filed Critical Universita degli Studi di Milano
Publication of EP1746982A2 publication Critical patent/EP1746982A2/en
Withdrawn legal-status Critical Current

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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • HDAC histone deacetylases
  • the currently available treatments for reducing cholesterol levels are mainly represented by inhibitors of the enzyme ⁇ -hydroxy- ⁇ -methylglutaryl-CoA (HMG-CoA) reductase (statins) and by PPAR nuclear receptor ligands.
  • HMG-CoA ⁇ -hydroxy- ⁇ -methylglutaryl-CoA
  • statins PPAR nuclear receptor ligands.
  • PPAR nuclear receptor ligands PPAR nuclear receptor ligands.
  • a promising field is represented by the cholesterol excretion pathways, through its conversion to bile acids.
  • the molecular mechanisms regulating this metabolic pathway are an ideal target for the development of novel therapeutic approaches .
  • the biosynthesis of bile acids represents the major cholesterol excretory pathway in mammals.
  • the gene encoding cholesterol 7 ⁇ -hydroxylase ( CYP7A1 ) , the enzyme regulating the conversion of cholesterol into bile acids, is negatively regulated at the transcriptional level by bile acids returning to the liver through the enterohepatic cycle.
  • Bile acids exert their effects by promoting the dissociation of transcription coactivators [e.g. PPAR ⁇ -coactivator-1 (PGC-1) and cAMP Response Element Binding protein (CREB) Binding Protein (CBP) ] from the promoter of the cholesterol 7 -hydroxylase gene, with the simultaneous recruitment of transcription corepressors and specific histone deacetylases to the cholesterol 7 ⁇ -hydroxylase gene promoter.
  • transcription coactivators e.g. PPAR ⁇ -coactivator-1 (PGC-1) and cAMP Response Element Binding protein (CREB) Binding Protein (CBP)
  • inhibitors of histone deacetylases provides reductions in plasma and hepatic triglycerides, as well as loss of body mass.
  • the principal classes of inhibitors of histone deacetylases are indicated hereinafter.
  • One first class of inhibitors of histone deacetylases used in the present invention are the compounds of- formula (I) and the pharmaceutically acceptable salts and solvates thereof:
  • the compounds of formula (I) of the present invention may be optically active, both as R and S enantiomers, or racemic mixtures or mixtures of diastereoisomers .
  • butyric acid, phenylbutyric acid and valproic acid belong to this category. Belonging to a second class of molecules are the compounds of formula (II) and the pharmaceutically acceptable salts and solvates thereof:
  • R 2 is linear or branched (Ci- 20 ) alkyl; linear or branched (Ci_ 2 o) alkenyl; linear or branched carbonyl (Ci-i ⁇ ) alkyl; linear or branched carbonyl (Ci-i ⁇ ) alkenyl; alkynyl (C ⁇ _ 6 ) alkyl; alkynyl (C ⁇ - ⁇ ) alkenyl; (C ⁇ _ ⁇ 6 ) alkyl-CO-NH;
  • A is single ring or condensed ring aryl or heteroaryl, either non substituted or substituted in any position by NR 3 R 4 ; CO-NH-OH; NH-S0 2 -R 5 ; (C ⁇ _ 4 ) alkoxy; linear or branched (Ci-4) alkyl; linear or branched (C 1 -4) alkenyl; halo; cyano; nitro; trifluoromethyl.
  • it is a heterocycle selected
  • thiophene furan, pyrole, imidazole, thiazole, oxazole, pyridine, pyrimidine, pyrazine, pyridazine, 1, 2, 4-triazine, 1, 2, 4, 5-tetrazine, either non substituted or substituted with one or more substituent groups selected from halo, hydroxy, nitro, cyano, (C 1 - 4 ) alkoxy, trifluoromethyl.
  • R 3 and R 4 are H; linear or branched (C ⁇ _ 6 ) alkyl; linear ' or branched (Ci- ⁇ ) alkenyl; saturated or unsaturated 5 or 6 member rings.
  • R 5 is linear or branched (C ⁇ _ 6 ) alkyl; aryl either non substituted or substituted with (C ⁇ _ 4 ) alkoxy; linear or branched (C1-4) alkyl; linear or branched (C ⁇ _ 4 ) alkenyl; halo; cyano; nitro; trifluoromethyl.
  • the compounds of formula (II) of the present invention may be optically active, both as R and S enantiomers, or racemic mixtures or mixtures of diastereoisomers .
  • tricostatin A scriptaid, pyroxamide, suberoylanilide hydroxamic acid (SAHA) , m- carboxycinnamic acid bis-hydroxamide (CBHA) , oxamflatin and:
  • Belonging to a third class of molecules are the compounds of formula (III) and the pharmaceutically acceptable salts and solvates thereof:
  • R 6 , R 7 , R 8 , R 9 are: H; linear or branched (Ci- ⁇ ) alkyl; linear or branched (CI- ⁇ ) alkenyl; (C ⁇ _ ⁇ o) alkylaryl either non substituted or substituted with (C ⁇ _ 4 ) alkoxy, linear or branched (C1- 4 ) alkyl, linear or branched (C ⁇ _ 4 ) alkenyl, halo, cyano, nitro, trifluoromethyl .
  • R 11 , R 12 , R 13 , R 16 , R 19 are: H; (C ⁇ _ 16 ) alkylaryl either non substituted or substituted with (C 1 - 4 ) alkoxy, linear or branched (C1-4) alkyl; (C ⁇ - ⁇ 6 ) alkyl carbonyl epoxyl; (Ci-i 6 ) .alkyl-CO-NH-OH; linear or ' branched (C ⁇ _ ⁇ 6 ) alkyl; linear or branched (Ci-ie) alkenyl; -CH 2 -S-CH 3 ; -(CH 2 ) -S- CH 3 ; (Ci-ie) alkylheterocyclyl (wherein the heterocycle is selected from: thiophene, furan, pyrole, imidazole, thiazole, oxazole, pyridine, indole N-substituted with (C ⁇ - 4 ) alkoxyl, (Ci-
  • R 6 , R 7 , R 8 , R 9 may form closed rings with R 12 R 11 , R 13 , R 19 respectively (in the latter case R 1S is H) , to give a saturated 5 or 6 member ring.
  • R 10 is a carbon atom.
  • R 10 may be a carbon atom or is:
  • R 18 is a (C ⁇ -io) alkyl or (Cs-10) alkenyl chain containing a disulphide bond, and is terminated by bonding to CR 11 ;
  • R 17 and R 20 are H, linear or branched (C ⁇ -6) alkyl; linear or branched (C ⁇ _s) alkenyl.
  • the compounds of formula (III) of the present invention may be optically active, both as R and S enantiomers, or racemic mixtures or mixtures of diastereoisomers .
  • belonging to this category are the following compounds: trapoxin A and B, HC-toxin, chlamydocin, apicidin, depsipeptide (also known as
  • Aoe 2-ammino-9, 10-epoxy-8-oxodecanoic acid and Tyr(Me), lie and Pip are as described hereinafter.
  • Other compounds belonging to this category are the so-called "CHAPs (cyclic Hydroxamic acid-containing peptide") , trapoxin derivatives wherein the terminal epoxyketone group is replaced with a hydroxamic acid
  • Examples of compounds belonging to the CHAPs family include : cyclo (Asu (NHOH) -Phe-Phe-D-Pro) (CHAP1) , cyclo (Asu (NHOH) -D-Tyr (Me) -lie-Pip) (CHAP49) , cyclo (Asu (NHOH) -D-Tyr (Me) -He-Pro) (CHAP30) , cyclo (Asu (NHOH) -D-Phe-Leu-Pip) (CHAP53) , cyclo (As (NHOH) -Aib-Phe-D-Pro) (CHAP15) , cyclo (Asu (NHOH) -D-Pro-Ala-D-Ala) (CHAP13) , cyclo (-L-Asu (NHOH) -D-Tyr (Me) -L-Ile-D-Pip) (CHAP50) ,
  • a ino acid sequences are expressed from the amino terminal end, using the standard three letter codes (Ala, Phe, Pro, lie); Tyr(Me) is the aminoacid tyrosine in which the phenolic OH group is replaced by OMe .
  • the expression "cyclo" means that the amino terminal end and the COOH-terminal have combined to form an amide bond.
  • ' NHOH in brackets means that the hydroxamic acid residue is located at the end of the Asu side chain.
  • R 23 is linear or branched (C ⁇ - 6 ) alkyl; linear or branched (C ⁇ - ⁇ ) alkenyl.
  • the compounds of formula (IV) of the present invention may be optically active, both as R and S enantiomers, or racemic mixtures or mixtures of diastereoiso ers .
  • depudesin belongs to this category.
  • Belonging to a fifth class of molecules are the compounds of formula (V) and the pharmaceutically acceptable salts and solvates thereof:
  • Formula (V) n 0, 1 wherein R 25 is NR 26 R 27 ; a hydroxyl group; a carboxylic group; halo; cyano; nitro and R 26 and R 27 are H; linear or branched (Ci- ⁇ ) alkyl; linear or branched (C ⁇ _ 6 ) alkenyl; saturated or aromatic 5 or 6 member rings .
  • R 24 is H; linear or branched (Ci-e) alkyl; linear or branched (C ⁇ - 6 ) alkenyl; a saturated or aromatic 5 or 6 member .ring; or is COOR 28 or COR 29 wherein R 28 and R 29 are selected from linear or branched (Ci- ⁇ ) alkyl; linear or branched (C ⁇ - 6 ) alkenyl; (C ⁇ _ ⁇ 6 ) alkylaryl; (C ⁇ _ ⁇ 6 ) alkylheteroaryl .
  • the compounds of formula (V) of the present invention may be optically active, both as R and S enantiomers, or racemic mixtures or mixtures of diastereoisomers .
  • members of this category include: N- acetyldinaline (also known as CI-994) and MS-275.
  • MS-275 has the following structural formula:
  • histone deacetylases are generally metalloenzy es, with a zinc atom at the active site, compounds possessing the ability to bind zinc, for example carboxylic groups, hydroxamic groups, alpha- ketothio groups etc., are potential HDAC inhibitors.
  • the formulae of such compounds and their histone deacetylase inhibitory activities are known in the state of the art.
  • histone deacetylases are also involved in the biochemical mechanisms regulating cellular growth
  • inhibitors thereof are used in the treatment of pathologies such as: various tumour types (leukaemias, solid tumours, haematopoietic tissue tumours etc.), psoriasis, haematological disorders, haemoglobinopathies, spinal muscular atrophy, Huntington's disease, genetic metabolic disorders (cystic fibrosis, adrenoleukodystrophy etc.).
  • WO03099789 WO0250244, US6638530, WO02076941, WO03099760, WO03099272, GB2389365, WO03092686, WO03087066, WO03082288, WO03076430, WO03076422, WO03076395, US2003078216, EP1307784.
  • Other pathologies which may be cured through the administration of HDAC inhibitors are cardiac hypertrophy (US200314434) , liver fibrosis and hepatic cirrhosis (WO03076438) .
  • the present invention relates to the use of inhibitors of histone deacetylase (HDAC) for the preparation of a medicament for the control of plasma cholesterol levels.
  • HDAC histone deacetylase
  • the invention relates to the use of inhibitors of histone deacetylase for the preparation of a medicament for the control of plasma and hepatic triglyceride levels .
  • the present invention relates to the use of inhibitors of histone deacetylase for the preparation of a medicament for the treatment of conditions mediated by cholesterol 7 ⁇ -hydroxylase activation.
  • cholesterol 7 ⁇ -hydroxylase activation is meant, particularly, but not exclusively, stimulation of transcription of the cholesterol 7 ⁇ - hydroxylase gene.
  • the present invention relates to the use of inhibitors of histone deacetylases (HDAC) for the preparation of a medicament for the treatment of diseases such as hyperlipidaemias (particularly hypercholesterolaemia) atherosclerosis, obesity, diabetes and metabolic syndromes and the prevention of cardiovascular and cerebrovascular pathologies, such as myocardial infarction or stroke.
  • HDAC histone deacetylases
  • the present invention relates to the use of HDAC inhibitors selected from the compounds belonging to the groups described by formulae (I) , (II) , (III), (IV) and (V) .
  • the preferred inhibitors belonging to said groups are: tricostatin A, phenylbutyrate, scriptaid, apicidin, pyroxamide, depsipeptide .
  • histone deacetylase inhibitors employed for the uses according to the invention are listed hereinafter: pivaloyloxymethylbutyrate (also known as AN-9) ; cyclostellettamine, particularly cyclostellettamine A, cyclostellettamine G, dehydrocyclostellettamme D and dehydrocyclostellettamme E (Naoya Oku et al . ; Bioorganic and Medicinal Chemistry Letters 14, 2004, 2617-2620); hydroxamic acids having the following structural formulae:
  • Examples of compounds belonging to this class include : cyclo (-L-Lys (For, OH) -D-Tyr (Me) -L-Ile-L-Pip) , cyclo (-L-Lys (For, OH) -D-Tyr (Me) -L-Ile-D-Pip) , cyclo (-L-Hly (For, OH) -D-Tyr (Me) -L-Ile-L-Pip) , cyclo (-L-Hly (For, OH) -D-Tyr (Me) -L-Ile-D-Pip) , cyclo (-L-Aoc (For, OH) -D-Tyr (Me) -L-Ile-L-Pip) , cyclo (-L-Aoc (For, OH) -D-Tyr (Me) -L-Ile-L-
  • the invention provides a pharmaceutical formulation comprising one or more of the previously described compounds, or a physiologically acceptable derivative thereof together with one or more physiologically acceptable carriers and, optionally, other therapeutic and/or prophylactic components.
  • the carriers or excipients must be "acceptable” in the sense that they must be compatible with ' the other components of the formula and not harmful to the recipient.
  • physiologically acceptable derivative is meant any physiologically acceptable salt or solvate, ester, or solvate of said ester, of a compound of the invention or any other compound which, by administration to the recipient, is capable of providing (either directly or indirectly) a compound of the invention or an active metabolite or residue thereof.
  • the preferred physiologically acceptable derivatives of the compounds of the invention are the pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include those derived from organic or inorganic bases.
  • the base derived salts include the salts of alkaline metals (for example sodium) , alkaline earth metals (for example magnesium) , ammonium and NR4+ (wherein R is Cl-4 alkyl) .
  • the compounds to be used, according to the present invention may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form which is suitable for administration by inhalation or insufflation (either through the mouth or nose) .
  • the pharmaceutical compositions may be, for example, in the form of tablets or capsules, prepared in the conventional manner with the aid of pharmaceutically acceptable excipients such as binding agents (for example pre-gelatinised corn starch, polyvmylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (for example lactose, macrocrystalline cellulose or calcium hydrogen phosphate) ; lubricants (for example magnesium stearate, talc or silica) ; disintegrants (for example potato starch or sodium starch glycolate) ; or inhibiting agents (for example sodium dodecyl sulphate) .
  • binding agents for example pre-gelatinised corn starch, polyvmylpyrrolidone or hydroxypropyl methylcellulose
  • Liquid preparations for oral administration may be, for example, in the form of solutions, syrups ' or suspensions or may be as lyophilised products to be reconstituted, prior to use, with water or other suitable carriers.
  • Such liquid preparations may be prepared using conventional methods with pharmaceutically acceptable additives such as suspension agents (for example sorbitol syrup, cellulose derivatives or hydrogenated edible fats) ; 'emulsifiers (for example lecithin or acacia) ; non- aqueous carriers (for example almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) ; and preservatives (for example methyl- or propyl-p- hydroxybenzoates or sorbic acid) . Preparations may also suitably contain flavourings, dyes and sweeteners.
  • Preparations for oral administration may be suitably formulated to allow the controlled release of the active ingredient.
  • Compositions for buccal administration may be in the form of conventionally formulated tablets or lozenges.
  • the compounds according to the present invention may be formulated for parenteral administration by injection.
  • Formulations for injections may be presented in single dose form, for example in vials, with added preservative.
  • the compositions may be presented in the aforementioned form as suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulary agents such as suspension agents, stabilisers and/or dispersants.
  • the active ingredient may be in powder form for reconstitution, prior to use, using a suitable carrier, for example sterile water.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example containing common basic suppository components such as cocoa butter or other glycerides .
  • the compounds may also be formulated as deposit preparations. Such long acting preparations may be administered as implants (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for , example in the form of an emulsion in a suitable oil) or ion exchange resin or as sparingly soluble derivatives, for example as a sparingly soluble salt.
  • the dosage of the compounds suggested for administration in humans ranges from 0.1 mg to 1 g and, preferably from 1 mg to 100 mg of the active ingredient per unit dose.
  • the unit dose may be administered, for example, from 1 to 4 times daily.
  • the dose will depend on the route selected for administration. It should be considered that it might be necessary to make continual adjustments to the dosage depending on the age and weight of the patient, in addition to the seriousness of the clinical condition to be treated.
  • the exact dose and the administration route will finally be at the discretion of the physician or veterinarian .
  • EXPERIMENTAL DATA AND EXAMPLES Our cellular model assays using the technique known as the "chromatin immunoprecipitation assay" indicate that bile acids cause rapid localised deacetylation of histones (Figure 1A). and the nuclear receptor Hepatocyte Nuclear Factor-4 (HNF-4) ( Figure IB) present in one specific region of the cholesterol 7 ⁇ -hydroxylase gene promoter.
  • HDAC histone deacetylase
  • bile acids cause the selective recruitment of histone deacetylases 1, 3 and 7 to the promoter region of the cholesterol 7 ⁇ -hydroxylase gene.
  • histone deacetylase 7 is translocated from the cytoplasm to the nucleus, where it exerts its inhibitory action.
  • bile acids cause the intranuclear localisation of histone deacetylase 7, which in turn promotes the recruitment of histone deacetylases 1 and 3, in addition to the simultaneous recruitment of the transcription corepressors, to the promoter region of the cholesterol 7 -hydroxylase gene.
  • histone deacetylase inhibitors such as valproic acid or tricostatin, may prevent inhibition of transcription of the cholesterol 7 ⁇ -hydroxylase gene.
  • histone deacetylase inhibitors such as for example valproic acid and tricostatin A
  • valproic acid and tricostatin A cancel out the inhibitory effect of bile acids on cholesterol 7 ⁇ -hydroxylase mRNA levels (figure 2), while the phosphoenolpyruvate carboxykinase gene (a key enzyme in hepatic gluconeogenesis) , used here as a negative control, continues to be repressed by bile acids, despite the addition of valproic acid or tricostatin A.
  • HDAC7 histone deacetylase 7
  • CYP7A1 the rate-limiting enzyme in the pathway for the conversion of cholesterol to bile acids
  • the "small interfering RNA (siRNA)" oligonucleotides may be administered to patients for the treatment of pathologies such as hypercholesterolaemias, hypertriglyceridaemias, atherosclerosis, diabetes, obesity, metabolic syndromes and for the prevention of cardiovascular and cerebrovascular pathologies and Alzheimer's disease.
  • pathologies such as hypercholesterolaemias, hypertriglyceridaemias, atherosclerosis, diabetes, obesity, metabolic syndromes and for the prevention of cardiovascular and cerebrovascular pathologies and Alzheimer's disease.
  • pathologies such as hypercholesterolaemias, hypertriglyceridaemias, atherosclerosis, diabetes, obesity, metabolic syndromes and for the prevention of cardiovascular and cerebrovascular pathologies and Alzheimer's disease.
  • pathologies such as hypercholesterolaemias, hypertriglyceridaemias, atherosclerosis, diabetes, obesity, metabolic syndromes and for the prevention of cardiovascular and cerebrovascular pathologies and Alzheimer's disease.
  • HDAC inhibitors used were valproic acid and tricostatin A, two structurally unrelated molecules.
  • the in vivo results obtained using this animal model show a significant increase in cholesterol 7 ⁇ -hydroxylase mRNA levels, as well as increased bile acid synthesis, measured as faecal excretion, in both valproic acid and tricostatin A treated animals ( Figure 4A) .
  • HDAC inhibitors cause marked reductions in plasma cholesterol (Figure 4B) and LDL (Figure 4C) levels; analysis of a narrow panel of ' genes involved in lipid and glucose metabolism has shown that histone deacetylase inhibitors do not significantly alter the levels ⁇ of mRNA for such genes, hence the hypocholesterolemizing effect is to be principally attributed to the derepression of the cholesterol 7 -hydroxylase gene, responsible for the conversion of cholesterol to bile acids ( Figure 4D) .
  • the administration of valproic acid and tricostatin A in the same animals also leads to reductions in plasma and hepatic triglycerides.
  • VPA valproic acid
  • TSA tricostatin
  • histone deacetylases 1, 3 and 7 selectively recruited onto the promoter of the cholesterol 7 -hydroxylase gene, ultimately represent novel molecular targets for new molecules having hypocholesterolemizing actions.
  • Selective inhibitors of histone deacetylases may assume a role as drugs for preventing atherosclerosis and the associated risk of cardiovascular and cerebrovascular diseases.
  • such molecules may also have- a protective role in relation to this pathology.
  • the histone deacetylases are currently the targets for the treatment of various types of tumours.
  • HepG2 hepatic cell cultures have been treated with the bile acid chenodeoxycholic acid for the times indicated in the figure.
  • 10 the acetylation states of histones H3 and H4 in the promoter of the gene encoding cholesterol 7 ⁇ -hydroxylase (panel A) , the amount of HNF-4 associated with the same promoter and its degree of acetylation (panel B) have been assessed using the "chromatin immunoprecipitation 15 assay".
  • mice have been treated with intraperitoneal injections of isotonic saline (controls) , with 200 mg/kg of body weight twice daily of valproic acid (VPA) , or with 1 mg/kg of body weight once daily of tricostatin A (TSA) .
  • the duration of the treatment was 7 days.
  • liver cholesterol 7 ⁇ -hydroxylase mRNA levels (panel A) and the faecal excretion of bile acids, as an indicator of their synthesis (panel A) , total plasma cholesterol levels (panel B) , the cholesterol content in the plasma lipoprotein fractions (panel C) and levels of the hepatic mRNA of the genes indicated (panel D) have been measured.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP05742909A 2004-04-30 2005-04-29 Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis and cardiovascular diseases Withdrawn EP1746982A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000876A ITMI20040876A1 (it) 2004-04-30 2004-04-30 Inibitori delle istone deacetilasi-hdac-quali agenti ipolipidemizzati per la terapia e la prevenzione dell'arteriosclerosi e malattie cardiovascolari
PCT/IT2005/000248 WO2005105066A2 (en) 2004-04-30 2005-04-29 Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis, cardiovascular diseases

Publications (1)

Publication Number Publication Date
EP1746982A2 true EP1746982A2 (en) 2007-01-31

Family

ID=34979580

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05742909A Withdrawn EP1746982A2 (en) 2004-04-30 2005-04-29 Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis and cardiovascular diseases

Country Status (3)

Country Link
EP (1) EP1746982A2 (it)
IT (1) ITMI20040876A1 (it)
WO (1) WO2005105066A2 (it)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11453661B2 (en) 2019-09-27 2022-09-27 Takeda Pharmaceutical Company Limited Heterocyclic compound

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100137239A1 (en) 2006-04-24 2010-06-03 Gloucester Pharmaceuticals Gemcitabine combination therapy
WO2007146730A2 (en) 2006-06-08 2007-12-21 Gloucester Pharmaceuticals Deacetylase inhibitor therapy
AU2007342028B2 (en) 2006-12-29 2013-06-13 Celgene Corporation Purifiction of romidepsin
WO2008090534A1 (en) * 2007-01-26 2008-07-31 Berand Limited Methods and compositions for inhibition of excessive weight gain, reduction of inappropriate eating behaviours and inhibition of binge eating for the treatment of obesity
KR100909867B1 (ko) * 2007-04-16 2009-07-29 주식회사바이오러넥스 골대사성 질환의 예방 및 치료를 위한 조성물
WO2011127482A2 (en) * 2010-04-09 2011-10-13 The Salk Institute For Biological Studies Modulation of histone deacetylases for the treatment of metabolic disease, methods and compositions related thereto
EP2389932A1 (en) * 2010-05-28 2011-11-30 Lunamed AG Compositions for use in genetic disorders comprising 4-phenyl-butyric acid and its salts
RU2607634C2 (ru) 2010-07-12 2017-01-10 Селджин Корпорейшн Твердые формы ромидепсина и их применение
US8859502B2 (en) 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
AU2012226586B2 (en) * 2011-03-09 2017-04-13 Cereno Scientific Ab Compounds and methods for improving impaired endogenous fibrinolysis using histone deacetylase inhibitors
EP2599481A1 (en) * 2011-11-30 2013-06-05 Lunamed AG 4-phenylbutyric acid for the treatment or prevention of various diseases
AU2012362726A1 (en) * 2011-12-29 2014-07-24 Pharmacyclics Llc Cinnamic acid hydroxyamides as inhibitors of histone deacetylase 8
AU2013202506B2 (en) 2012-09-07 2015-06-18 Celgene Corporation Resistance biomarkers for hdac inhibitors
AU2013202507B9 (en) 2012-11-14 2015-08-13 Celgene Corporation Inhibition of drug resistant cancer cells
NZ630311A (en) 2013-12-27 2016-03-31 Celgene Corp Romidepsin formulations and uses thereof
GB201417828D0 (en) 2014-10-08 2014-11-19 Cereno Scient Ab New methods and compositions
CN114209667A (zh) 2016-04-08 2022-03-22 赛伦诺科技有限公司 包含丙戊酸的延迟释放药物制剂和其用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6025369A (en) * 1996-05-03 2000-02-15 The Board Of Regents Of The University Nebraska N-methyl-D-aspartate (NMDA) receptor blockers for the prevention of atherosclerosis
MXPA01010933A (es) * 1999-04-29 2002-06-21 Merck Patent Gmbh Inhibidores del sistema de clivaje de la glicina como potenciales antipsicoticos.
US6987131B1 (en) * 2000-06-26 2006-01-17 Burzynski Stanislaw R Phenylacetic acid compositions for treating or preventing hypercholesterolemia
US6191117B1 (en) * 2000-07-10 2001-02-20 Walter E. Kozachuk Methods of producing weight loss and treatment of obesity
US6884421B2 (en) * 2002-03-27 2005-04-26 Council Of Scientific And Industrial Research Pharmaceutical composition for diabetic nephropathy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005105066A2 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11453661B2 (en) 2019-09-27 2022-09-27 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11958845B2 (en) 2019-09-27 2024-04-16 Takeda Pharmaceutical Company Limited Heterocyclic compound

Also Published As

Publication number Publication date
WO2005105066A8 (en) 2006-04-13
WO2005105066A3 (en) 2006-05-18
ITMI20040876A1 (it) 2004-07-30
WO2005105066A2 (en) 2005-11-10

Similar Documents

Publication Publication Date Title
WO2005105066A2 (en) Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis, cardiovascular diseases
US11931336B2 (en) Enhancing autophagy or increasing longevity by administration of urolithins
US10363237B2 (en) Compositions and methods of inhibiting N-acylethanolamine-hydrolyzing acid amidase
CA3005760A1 (en) Compounds and methods for inhibiting production of trimethylamine
WO2007001150A2 (en) Method for preventing and treating conditions mediated by ppar using macelignan
JP2021507944A (ja) 運動ニューロン疾患を含む神経障害のための組成物および治療方法
CA2522738A1 (en) Compounds for the treatment of metabolic disorders
JP5246834B2 (ja) アディポネクチン産生強化剤
CN102149702A (zh) 新型亚甲二氧基酚化合物和其治疗疾病的用途
WO2022082079A1 (en) Metalloenzyme inhibitors for treating cancers, alzheimer's disease, hemochromatosis, and other disorders
US7727977B2 (en) Kynurenine 3-hydroxylase inhibitors for the treatment of diabetes
KR102662117B1 (ko) 미생물 유래 대사물질 그라피스락톤 a를 유효성분으로 함유하는 비만 또는 비알콜성 지방간질환의 예방 또는 치료용 약학적 조성물
Kharbanda et al. In silico designing, in vitro and in vivo evaluation of potential PPAR-γ agonists derived from aryl propionic acid scaffold
WO2000040087A1 (en) Converting cox inhibition compounds that are not cox-2 selective inhibitors to derivatives that are cox-2 selective inhibitors
JP2002529409A (ja) グルコース及び脂質低下化合物類
JP2021533190A (ja) ＬＤＬコレステロールの細胞内クリアランスを増強しかつスタチンとの併用療法で効力を高めかつ副作用を減らすための、カルバメートβフェニルエタノールアミン類似体の新規使用法
Wang et al. Drug discovery targeting thyroid hormone receptor β (THRβ) for the treatment of liver diseases and other medical indications
CN116999567A (zh) 二硒键桥连的治疗肝病的响应型药物及其制法和用途
CN115607546A (zh) Isarubrolone C、包含Isarubrolone C的药物组合物及应用
KR20020071650A (ko) 3-(4'-히드록실-3',5'-디메톡시페닐)프로피온산, 이의 유도체 및 이의 제조방법 및 이를 함유하는 ＨＭＧ-ＣｏＡ 환원효소 저해제
KR20090093246A (ko) 유크레스타 홀스필디 추출물을 유효성분으로 함유하는피파알파에 의해 매개되는 질환의 예방 또는 치료용 조성물

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20061122

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20070704

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20091103