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    • 专利摘要:
    The present invention relates to AceFaPC (1-Acetyl-2-Fattyacyl-glycero-PhosphoCholine) for its use in the prevention and treatment of diseases associated with acetylcholine deficiency. The invention also relates to the AceFaPC molecule, for which Fa represents an unsaturated acyl comprising at least 14 carbon atoms, and the pharmaceutical compositions comprising it.
    公开号:FR3063645A1
    申请号:FR1751880
    申请日:2017-03-08
    公开日:2018-09-14
    发明作者:Michel Lagarde；Evelyne Vericel；Madeleine Picq；Michel Guichardant；Nathalie Bernoud-Hubac；Baptiste Fourmaux
    申请人:Lipther；Universite Claude Bernard Lyon 1 UCBL；Institut National de la Recherche Agronomique INRA；Institut National de la Sante et de la Recherche Medicale INSERM；Institut National des Sciences Appliquees de Lyon ；
    IPC主号:
    专利说明:

    Holder (s): lipther. National institute of APPLIED sciences of LYON. UNIVERSITY CLAUDE BERNARD LYON 1. NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH, NATIONAL INSTITUTE OF AGRONOMIC RESEARCH.
    Extension request (s)
    Agent (s): LTL SAS.
    Pty ACEFAPC FOR THE TREATMENT OF DEPENDENT ACETYLCHOLINE DISEASES.
    The present invention relates to AceFaPC (1-Acetyl2-Fattyacyl-glyceroPhosphoCholine) for use in the prevention and treatment of diseases associated with acetylcholine deficiency. The invention also relates to the AceFaPC molecule, for which Fa represents an unsaturated acyl comprising at least 14 carbon atoms, and the pharmaceutical compositions comprising it.
    FR 3 063 645 - A1
    AceFaPC FOR THE TREATMENT OF DEPENDENT ACETYLCHOLINE DISEASES
    FIELD OF THE INVENTION
    The present invention relates to AceFaPC (1-Acetyl-2-FattyacylglyceroPhosphoCholine) for use in the prevention and treatment of diseases associated with acetylcholine deficiency. The invention also relates to the AceFaPC molecule, for which Fa represents an unsaturated acyl comprising at least 14 carbon atoms, and the pharmaceutical compositions comprising it.
    STATE OF THE ART
    AceDoPC or 1-acetyl, 2-docosahexaénoyl-phosphatidylcholine is a transporter of docosahexaenoic acid (DHA) well known to those skilled in the art whose enzymatic synthesis is described in application WO 2008/068413. It has been shown in particular that the passage of a reconstituted blood-brain barrier is favored with AceDoPC, in comparison with non-esterified DHA or PC-DHA (Hachem M. & al., Mol. Neurobiol. 2016) . The same study showed that AceDoPC used as a transporter of DHA in the brain could prevent the extension of brain damage when injected into rats having suffered an ischemic stroke (Lagarde M. & al., OCL 2016, 23 (1) D102). While only the treatment of ischemia has been studied in vivo in a rat model, the use of AceDoPC as a supplier of DHA to the brain is envisaged in relation to neurological diseases associated with DHA deficiency (Hachem M. & al., Mol Neurobiol., 2016, 53 (5), 3205-15). The link between DHA and prevention of Alzheimer's disease has been raised, in particular because patients with Alzheimer's disease have a DHA deficiency. Thus a DHA transporter such as AceDoPC could be considered to promote the prevention of Alzheimer's disease but not to treat it.
    While studies have focused on the transport and supply of DHA, the inventors have today highlighted that AceDoPC and in general AceFaPC, for which Fa is an acyl radical of unsaturated fatty acid d 'at least 14 carbon atoms can quickly transfer its acetyl group to a substrate comprising an alcohol, in particular primary.
    Based on this observation, the inventors envisaged AceDoPC, no longer as a transporter of DHA, but as a supplier of acetyl. Then, since AceDoPC also includes a choline group, the inventors then considered the possibility of producing acetylcholine from AceDoPC, in environments which are poor in sources of choline and / or acetyl. This has been confirmed by various experiments which make it possible to consider using AceDoPC and more generally AceFaPC to treat diseases associated with acetylcholine deficiency.
    STATEMENT OF THE INVENTION
    The present invention therefore relates to AceFaPC of general formula (I) ch 2 -o-co-ch 3
    CH, O CH 2 -R l II h 3 cn + -ch 2 -ch 2 -opo-ch 2
    CH, 0 3 (1) in which R represents the acyl radical of an unsaturated fatty acid comprising at least 14 carbon atoms, for its use in the prevention and treatment of diseases associated with acetylcholine deficiency.
    The invention also relates to an AceFaPC of formula (I ’)
    CH 2 -O-CO-CH 3
    CH- O CH 2 -R '
    I II h 3 cn + -ch 2 -ch 2 -opo-ch 2
    CH- 0 3 (l ') in which R' represents the acyl radical of an unsaturated fatty acid comprising at least 14 carbon atoms with the exception of the acyl radical of DHA.
    The invention also relates to a mixture of AceFaPC of formula (I ') and AceDoPC, as well as a pharmaceutical composition comprising an AceFaPC of formula (I') alone or in mixture with AceDoPC and an appropriate excipient. for his administration.
    DETAILED DESCRIPTION OF THE INVENTION
    The present invention therefore relates to AceFaPC of general formula (I)
    CH 2 -O-CO-CH 3
    CH- O CH 2 -R
    I II h 3 cn + -ch 2 -ch 2 -opo-ch 2
    CH, 0 (l) in which R represents the acyl radical of an unsaturated fatty acid comprising at least 14 carbon atoms, hydrates, pharmaceutically acceptable salts or pharmaceutically acceptable solvates.
    It relates to these AceFaPC of formula (I) for their use in the prevention and treatment, more particularly the treatment of diseases associated with an acetylcholine deficiency.
    The invention also relates to a method of treating or preventing a disease associated with acetylcholine deficiency in a patient which comprises administering to the said patient an appropriate dose of AceFaPC of formula (I) or a mixture of AceFaPC of formula (I).
    The invention is particularly suitable for the prevention and treatment, more particularly the treatment, of these diseases in humans. In particular, the treatment will be used once the patient has been identified as having an acetylcholine deficiency or likely to develop such a deficiency.
    Among the diseases associated with an acetylcholine deficiency, there may be mentioned in particular Alzheimer's disease associated with an acetylcholine deficiency in the brain, diseases of neuromuscular transmission in which an acetylcholine deficiency is recognized, in particular neuromuscular diseases, in particular myopathies with acetylcholine deficiency.
    By acetylcholine deficiency, or acetylcholine deficiency, we mean that the amount of acetylcholine measured in an organ of an individual is much lower than the normal expected in an individual who does not have this deficiency (or healthy individual). This substantial drop compared to a healthy individual leads to an imbalance or metabolic dysfunction of the organ.
    The invention therefore relates to the AceFaPC of formula (I), or a mixture of AceFaPC of formula (I), for their use in the treatment, more particularly the treatment of diseases associated with acetylcholine deficiency in a patient for whom the presence of such an acetylcholine deficiency has been identified beforehand.
    The invention also relates to a method of treating a disease associated with acetylcholine deficiency in a patient which includes
    a) the selection of patients in whom an acetylcholine deficiency has been identified, and
    b) the administration to said patient of an appropriate dose of AceFaPC of formula (I) or of a mixture of AceFaPC of formula (I).
    According to a preferred embodiment of the invention, AceFaPC should be administered so that it is substantially "intact" when it reaches the target organ in which acetylcholine is to be produced to prevent or counteract its deficiency. By substantially "intact" is meant that a sufficient amount of AceFaPC reaches the said organ without being altered, in particular by hydrolysis of acetyl.
    It has been observed that the loss of acetyl is favored in the gastrointestinal tract of mammals (WO 2017/006047). Therefore, the preferred modes of administration will be those which are suitable for avoiding the gastrointestinal tract. Mention will in particular be made of administration by the intravenous, intramuscular, subcutaneous, transdermal or inhalation route.
    For AceFaPC of formula (I), where R represents the acyl radical of an unsaturated fatty acid comprising at least 14 carbon atoms, the unsaturated fatty acid comprising at least 14 carbon atoms is advantageously a fatty acid of more than 18 carbon atoms which can go up to more than 22 carbon atoms, in particular 16, 20, 22 and 24 carbon atoms. These unsaturated fatty acids are preferably polyunsaturated. These unsaturated fatty acids are well known to those skilled in the art.
    They are particularly chosen from palmitoleic, oleic, linoleic (LA), alpha- or gamma-linolenic (ALA or GLA), arachidonic (ARA), adrenic (AdA) eicosapentaenoic (EPA), dihomo-gamma-linolenic, docosapentaenoic ( DPA) docosahexaenoic (DHA), erucic and nervonic.
    Preferably, the radical R of AceFaPC of formula (I) is the acyl radical of a polyunsaturated fatty acid chosen from linoleic (LA), alpha- or gamma-linolenic (ALA or GLA), arachidonic (ARA) acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA). Preferably, the R of AceFaPc of formula (I) is the acyl radical of a polyunsaturated fatty acid chosen from arachidonic acid (ARA), and docosahexaenoic acid (DHA). These favorite products are called AceArPC and AceDoPC, respectively.
    By "hydrates" is meant a compound in hydrated form. By way of example, mention may be made of semi-hydrates, monohydrates and polyhydrates.
    The salts of the compounds of formula (I) according to the present invention include those with acids or bases, depending on the substituents present. Mention may be made of the pharmaceutically acceptable salts, such as sodium, potassium and calcium salts.
    By "solvates" is meant a form of the compound associated with one or more solvent molecules, in particular used during its synthesis or during its purification, without however being in solution in the latter. The solvent in question will be pharmaceutically acceptable.
    By appropriate dose, or appropriate amount, according to the invention means any amount which makes it possible to increase the amount of acetylcholine and preferably to restore an amount of acetylcholine close to normal expected in a healthy individual. This appropriate dose can be taken once or several times, with repeated doses over time. Insofar as the disease treated is a chronic condition, treatment may be taken throughout the patient's life, the appropriate doses being adapted according to the course of the disease.
    The preparation of AceFaPC is known to those skilled in the art, in particular according to the method described in applications WO 2008/068413 or WO 2017/006047.
    For the prevention and treatment of diseases associated with acetylcholine deficiency, those skilled in the art may choose to use an AceFaPC alone or a mixture of AceFaPC. It may also combine AceFaPC or the mixture of AceFaPC with the usual treatments for diseases associated with acetylcholine deficiency.
    The invention also relates to a mixture of AceFaPC of formula (I) comprising at least two AceFaPC for which the radicals R are different, in all proportions.
    According to a preferred embodiment of the invention, at least one of the AceFaPCs of the mixture is AceDoPC. The preferred mixture according to the invention is therefore a mixture comprising at least one AceFaPC of formula (I) in which R is the acyl radical of a polyunsaturated fatty acid chosen from linoleic (LA), alpha- or gammalinolenic acids (ALA or GLA), arachidonic (ARA) and, eicosapentaenoic (EPA), preferably ARA, and AceDoPC, in all proportions.
    The invention also relates to a combination product, or “kit of parts”, for simultaneous or staggered use, which comprises on the one hand AceDoPC and on the other hand at least one AceFaPC of formula (I ) which is not AceDoPC, as defined above.
    The invention also relates to a pharmaceutical composition comprising at least one mixture of AceDoPC and at least one AceFaPC of formula (I) which is not AceDoPC and at least one pharmaceutically acceptable excipient.
    Those skilled in the art are well aware of the pharmaceutically acceptable excipients which may be used for the preparation of a pharmaceutical composition, in particular described in the reference works of the pharmacopoeia. It will preferably choose the excipients which will preserve the structure of AceFaPC for their conservation, in particular to prevent hydrolysis of acyl.
    The pharmaceutical compositions are preferably in a form suitable for intravenous, intramuscular, subcutaneous, transdermal or inhalation administration.
    DESCRIPTION OF THE FIGURES
    Figure 1 depicts the synthesis of acetylcholine from AceFaPC under the action of a phospholipase D.
    Figure 2 shows the detection of acetylcholine and its main fragmentation product by mass spectrometry.
    Figure 3 shows the percentages of blood flow to the brain (rat) based on radioactive DHA, as a function of time. (Hachem et al. Mol. Neurobiol. 2016)
    EXAMPLES
    Several experiments have been carried out using AceFaPC (DHA and oleic acid) as a possible precursor of acetylcholine and final measurement of the latter by radiochromatography or mass spectrometry.
    Example 1 Synthesis of Acetylcholine from AceFaPC with a Rat Brain Homogenate
    A rat brain homogenate was incubated with AceFaPC, labeled with 14 C on acetyl, in a Tris-HCl buffer pH 8 in the presence of a cocktail of anti-proteases and an inhibitor of acetylcholine esterase. Incubation takes place at 37 ° C for one hour. After extraction with an ethanol / chloroform mixture, the organic phase and the aqueous phase are separated and analyzed. After separation by thin layer chromatography, the products are visualized with a radioactivity reader. A radioactive spot corresponding to the migration of acetylcholine is detected. The incubation of a rat brain homogenate with labeled AceFaPC therefore allows the synthesis of radioactive acetylcholine, after release of choline by the cerebral phospholipase D and chemical coupling of this choline with an acetyl group labeled in sn- position. 1 of AceFaPC and / or coupling of radioactive acetyl provided by AceFaPC and endogenous choline.
    Example 2 Synthesis of Acetylcholine from AceFaPC with Phospholipase D
    The acellular incubation of AceFaPC was carried out in the presence of a microbial phospholipase D (from Streptomyces chromofuscus) in a Tris-HCI pH 8 buffer (brain pH) for one hour at 37 ° C. Following incubation, phospholipase D was destroyed by the addition of ethanol. After centrifugation, the ethanolic aqueous mixture was separated and evaporated to dryness. The residue was redissolved in the 95% acetonitrile / 5% ammonium formate mixture and then filtered by centrifugation. The detection of acetylcholine in the solution was made by mass spectrometry.
    Acetylcholine was detected both on the basis of its molecular mass (146) and that of its main fragmentation product (87: majority ion corresponding to the radical CH 3 -COO-CH 2 -CH 2 -) (Figure 2).
    In these cell-free experiments, two substrates were used by considering the lowest unsaturation for the acyl in position sn-2, namely the oleoyl radical (R 2 -COO-, Fig 1): AceOIPC and the strongest with the docosahexaénoyl radical : AceDoPC®. For AceOIPC, approximately 5% of the choline released has been converted to acetylcholine. For AceDoPC®, this conversion reached 36%. The reasons for this difference are unknown at this stage of the experiment. However, we can hypothesize that the conjugation of choline with the acetyl radical is better if the sn-2 position is less congested, which is the case for the docosahexaénoyl radical (with 6 double bonds) compared to the oleoyl radical (with a single double bond) because the folding of the acyl chain with 6 double bonds is much greater than for a single double bond. This result is particularly encouraging for AceFaPC containing polyunsaturated acyls, such as docosahexaénoyl and arachidonoyl (not yet tested), the two most important acyls of the brain.
    The acellular incubation of AceFaPC was also carried out in the presence of an equimolecular amount of choline chloride dissolved in a Tris-HCl pH 8 buffer for one hour at 37 ° C. with shaking. After evaporation to dryness under nitrogen, the residue was dissolved in the mixture of 95% acetonitrile / 5% ammonium formate. As previously described, after filtration by centrifugation, the measurement of acetylcholine was made by mass spectrometry.
    These experiments show that incubations of AceFaPC in the presence of phospholipase D (which releases choline from AceFaPC) or in the presence of exogenous choline allow the synthesis of acetylcholine.
    The proximity of the two constituent groups (acetyl and choline) of acetylcholine on the same molecule, spaced about one nm apart, is likely to facilitate their conjugation in the final product relative to the distance within the same cell ( distance of the order of pm) as is accepted in all the biochemical processes concerned by this proximity of the reactants.
    This proximity is summarized by the reaction shown in Figure 1.
    The results confirm that the hypothesis of the mechanism of action of transformation of AceFaPC into acetylcholine in the brain under the action of cerebral phospholipase D.
    Example 3: Transport of AceDoPC in the brains of rats (Hachem et al.
    2016)
    14 C-labeled AceDoPC on the docosahexaenoyl residue was injected into the bloodstream of different rats. After 1 h, 24 h and 48 h, the brains of the rats were analyzed to locate the radioactivity in different lipid compartments. With regard to AceDoPC, its radioactivity increased from 80% of the total injected after 1 hour, then 30% after 24 hours and 10% after 48 hours (Figure 3). These results confirm that the AceDoPC injected into the bloodstream is substantially "intact" when it reaches the brain where it is metabolized, in particular by the loss of its acetyl residue with the formation of acetylcholine.
    REFERENCES
    WO 2008/068413
    Hachem M. & al., Mol Neurobiol., 2016, 53 (5), 3205-15 Lagarde M. & al., OCL 2016, 23 (1) D102
    权利要求:
    Claims (8)
    [1" id="c-fr-0001]
    1. AceFaPC of general formula (I)
    CH 2 -O-CO-CH 3 '2 ch 2 -r ch 3 o (l) in which R represents the acyl radical of an unsaturated fatty acid comprising at least 14 carbon atoms, hydrates, pharmaceutically acceptable salts or pharmaceutically solvates acceptable for use in the prevention and treatment of diseases associated with acetylcholine deficiency.
    [2" id="c-fr-0002]
    2. AceFaPC according to claim 1, characterized in that the said disease associated with an acetylcholine deficiency is chosen from Alzheimer's disease and neuro-muscular diseases.
    [3" id="c-fr-0003]
    3. AceFaPC according to one of claims 1 or 2, characterized in that it is administered by an appropriate route to avoid the gastrointestinal tract.
    [4" id="c-fr-0004]
    4. AceFaPC according to claim 3, characterized in that it is administered intravenously, intramuscularly, subcutaneously, transdermally or by inhalation.
    [5" id="c-fr-0005]
    5. AceFaPC mixture characterized in that it comprises AceDoPC and at least one AceFaPC of formula (I) in which R represents an acyl acyl radical of an unsaturated fatty acid comprising at least 14 carbon atoms and R is not the acyl radical of DHA.
    [6" id="c-fr-0006]
    6. Mixture according to claim 5, characterized in that the unsaturated fatty acid of AceFaPC of formula (I) is chosen from oleic acid and arachidonic acid.
    [7" id="c-fr-0007]
    7. Pharmaceutical composition, characterized in that it comprises a mixture of AceFaPC according to one of claims 5 or 6 and at least one pharmaceutically acceptable excipient.
    [8" id="c-fr-0008]
    8. Composition according to claim 7, characterized in that it is in a form suitable for administration by intravenous, intramuscular, subcutaneous, transdermal or by inhalation route.
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    法律状态:
    2018-03-08| PLFP| Fee payment|Year of fee payment: 2 |
    2018-09-14| PLSC| Search report ready|Effective date: 20180914 |
    2020-03-31| PLFP| Fee payment|Year of fee payment: 4 |
    2020-12-11| CD| Change of name or company name|Owner name: INSTITUT NATIONAL DES SCIENCES APPLIQUEES DE L, FR Effective date: 20201103 Owner name: INSTITUT NATIONAL DE RECHERCHE POUR L'AGRICULT, FR Effective date: 20201103 Owner name: UNIVERSITE CLAUDE BERNARD LYON 1, FR Effective date: 20201103 Owner name: INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERC, FR Effective date: 20201103 Owner name: LIPTHER, FR Effective date: 20201103 |
    2021-03-30| PLFP| Fee payment|Year of fee payment: 5 |
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