WO2014170343A1 - Agents de dépolarisation et modulateurs du récepteur nicotinique de l'acétylcholine pour le traitement de troubles dopaminergiques - Google Patents

Agents de dépolarisation et modulateurs du récepteur nicotinique de l'acétylcholine pour le traitement de troubles dopaminergiques Download PDF

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WO2014170343A1
WO2014170343A1 PCT/EP2014/057661 EP2014057661W WO2014170343A1 WO 2014170343 A1 WO2014170343 A1 WO 2014170343A1 EP 2014057661 W EP2014057661 W EP 2014057661W WO 2014170343 A1 WO2014170343 A1 WO 2014170343A1
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receptor
agonist
neurons
composition
composition according
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PCT/EP2014/057661
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Patrick Pierre MICHEL
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Icm (Institut Du Cerveau Et De La Moelle Épinière)
Aphp (Assistance Publique - Hôpitaux De Paris)
Centre National De La Recherche Scientifique (Cnrs)
INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Pierre Et Marie Curie - Paris 6 (Upmc)
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Publication of WO2014170343A1 publication Critical patent/WO2014170343A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor

Definitions

  • the present invention relates to the treatment of Parkinson disease (PD) and other diseases, disorders or conditions related to dysfunction or death of dopamine (DA) neurons in the substantia nigra (SN). More specifically, the present invention relates to a composition comprising depolarizing agents such as, for example, the Orexin peptides, and modulators of the nicotinic cholinergic pathway acting on a receptor expressed by DA neurons of the SN,
  • the composition of the invention may be used, for protecting DA neurons in PD, in particular in patients developing REM sleep behavior disorder (RBD), a frequent prodrome of PD and related disorders.
  • RBD REM sleep behavior disorder
  • Parkinson Disease is a neurodegenerative disease of the central nervous system, resulting from the death of dopamine (DA) -generating cells in the substantia nigra (SN). PD is more common in the elderly, with most cases occurring after the age of 50.
  • DA dopamine
  • SN substantia nigra
  • PD patients experience motor symptoms, such as, for example, bradykinesia, tremor at rest, rigidity or stiffness, shaking, and postural instability; as well as non-motor neuron symptoms, including, without limitation, autonomic dysfunction, cognitive (impairment of cognitive and executive performances) and behavioral problems leading sometimes to dementia, emotional problems (mostly depression), sensory problems and sleep disorders.
  • motor symptoms such as, for example, bradykinesia, tremor at rest, rigidity or stiffness, shaking, and postural instability
  • non-motor neuron symptoms including, without limitation, autonomic dysfunction, cognitive (impairment of cognitive and executive performances) and behavioral problems leading sometimes to dementia, emotional problems (mostly depression), sensory problems and sleep disorders.
  • PD is usually preceded or accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behavior disorder (RBD), hallucinations and depression.
  • RBD REM sleep behavior disorder
  • Orexin-A and orexin-B are small neuropeptides that are derived from the cleavage of a common precursor prepro-orexin, produced in the lateral hypothalamus.
  • the orexin peptides are highly conserved between humans and mice, with identical OXA sequences and just two amino acid substitutions in OXB (Sakurai et al, Cell, 1998). These peptides operate through activation of two G-protein-coupled receptors, the 0X1 and 0X2 receptors (OX1R and OXR2, respectively).
  • orexin peptides are to regulate normal wakefulness, as loss of orexin-producing neurons causes narcolepsy in humans and rodents (Scammell and Winrow, Annu. Rev. Pharmacol. Toxicol. 2011).
  • a loss of orexin-containing neurons has been reported in the hypothalamus of PD patients (Fronczek et al, Brain, 2007; Thannickal et al, Brain, 2007) which may explain why a number of symptoms present in narcolepsy, i.e., daytime sleep attacks, nocturnal insomnia, hallucinations, REM sleep behavior disorder (RBD) are often associated to PD (Thannickal et al, Brain, 2007).
  • RBD REM sleep behavior disorder
  • the molecular mechanism that causes sleep disorders in PD may be linked to some extent to that causing DA cell demise in the SN of PD patients and that orexin peptides may be involved, directly or indirectly, in this process. Therefore, some treatments of sleep disorders comprising the administration of orexin peptides were suggested in the art.
  • the patent application WOO 1/74162 describes a method of treating a sleep disorder in a patient, especially of narcolepsy, wherein said method comprises administering to the patient an agonist of the hypocretin receptor, preferably OXA.
  • NIC depolarizing alkaloid nicotine
  • the present invention thus relates to a composition
  • a composition comprising orexin peptides and a modulator of nicotinic acetylcholine receptors (nAChRs), such as, for example, NIC for the treatment of PD associated dysfunction/degeneration of DA neurons in the SN, in particular at an early stage of the disease when patients develop prodromal signs such as RBD.
  • nAChRs nicotinic acetylcholine receptors
  • the experimental results obtained by the Inventors also support the use of such a composition for treating neuropsychiatric disorders wherein DA neurons of the SN and/or neighboring DA neurons of the ventral tegmental area are also dysfunctional.
  • One object of the invention is a composition
  • DA dopamine
  • SN substantia nigra
  • said depolarizing agent is an agonist of an orexin receptor.
  • the agonist of an orexin receptor is a selective agonist of the orexin receptor OX2R.
  • the agonist of an orexin receptor is an orexin peptide, preferably OXB.
  • said depolarizing agent is an agonist of a purinergic receptor, preferably P2XR.
  • said depolarizing agent is an agonist of a neurokinin receptor, preferably NK1 and/or NK3.
  • the modulator of the nicotinic cholinergic pathway is an agonist of a nAChR, more preferably an agonist of the cc7-nAChR.
  • said agonist of the cc7-nAChR is selected from the group comprising NIC, PNU 282,987, AR-RI7779, SSRI80711, JN403, ABBF, TC-5619, PHA-543613, SENI2333, TC-5619, GTS-21/DMXB-A, MEM3454, AZD0328, A- 582941, and mixtures thereof; preferably the agonist of the cc7 nAChRs is NIC or PNU 282,987.
  • Another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a composition as described here above and at least one pharmaceutically acceptable excipient.
  • Another object of the invention is a medicament comprising a composition as described here above.
  • Another object of the invention is a composition as described here above, a pharmaceutical composition as described here above or a medicament as described here above for providing neuroprotection to a subject in need thereof.
  • Another object of the invention is a composition as described here above, a pharmaceutical composition as described here above or a medicament as described here above for treating a disease, disorder or condition related to the dysfunction of the DA neurons of the SN in a subject in need thereof.
  • said disease, disorder or condition related to the dysfunction of the DA neurons of the SN is selected from the list comprising PD or other neurodegenerative disorders with parkinsonian syndromes, preferably PD, sleep disorders, deregulations of the sleep wake cycle, and neuropsychiatric diseases, disorders or conditions.
  • Another object of the invention is a composition as described here above, a pharmaceutical composition as described here above or a medicament as described here above for treating sleep disorders or deregulations of the sleep wake cycle associated with PD or another neurodegenerative disorder with parkinsonian syndromes, preferably PD.
  • the subject is affected with, is diagnosed with or is at risk of developing PD or another neurodegenerative disorder with parkinsonian syndromes, preferably PD.
  • Synergy defines the interaction of two or more agents acting together in a positive way to produce an effect that neither could produce alone.
  • An "additive synergy” defines a synergy wherein the combined effect of the agents is equal to the sum of the effects of each agent alone. When the combined effect is greater than the sum of the effects of each agent operating by itself, the synergy is referred as a "potentiating effect".
  • the synergy is an additive synergy. In another embodiment, the synergy is a potentiating effect.
  • Modulator refers to a compound that modulates the activity of the nicotinic cholinergic pathway.
  • a modulator is a compound whose administration leads to an activation of this pathway.
  • the said modulator may act on the expression and/or on the activity of a nAChR, preferably, the modulator acts on the activity of an nAChR.
  • Antagonist refers to a compound that binds to a receptor on a cell, thereby triggering a response by that cell.
  • An agonist usually mimics the action (i.e, induces a response that is of the same type, but not necessarily of the same order) of a naturally occurring substance that naturally binds to said receptor.
  • the binding of an agonist of a receptor on said receptor activates said receptor.
  • Treatment refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the disease, disorder or condition related to the dysfunction of the DA neurons of the SN.
  • Those in need of treatment include those already with the disease, disorder or condition related to the dysfunction of the DA neurons of the SN as well as those prone to develop the disease, disorder or condition related to the dysfunction of the DA neurons of the SN or those in whom the disease, disorder or condition related to the dysfunction of the DA neurons of the SN is to be prevented.
  • a subject or mammal is successfully "treated" for a disease, disorder or condition related to the dysfunction of the DA neurons of the SN if, after receiving a therapeutic amount of a composition according to the invention, the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the progression of dopaminergic deficits, such as, for example, using brain imaging approaches with specific radioligands; and/or relief to some extent, of one or more of the clinical symptoms associated with the disease, disorder or condition related to the dysfunction of the DA neurons in the SN, such as, for example, using a clinical rating scale to assess the spectrum of PD related symptoms; reduced morbidity and mortality, and improvement in quality of life issues.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by procedures familiar to research clinicians and/or physicians.
  • “Therapeutically effective amount” refers to the level or amount of agent that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of a disease, disorder or condition related to the dysfunction of the DA neurons of the SN; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of a disease, disorder or condition related to the dysfunction of the DA neurons of the SN; (3) bringing about ameliorations of the symptoms of a disease, disorder or condition related to the dysfunction of the DA neurons of the SN; (4) reducing the severity or incidence of a disease, disorder or condition related to the dysfunction of the DA neurons of the SN; or (5) curing a disease, disorder or condition related to the dysfunction of the DA neurons of the SN.
  • An effective amount may be administered prior to the onset of a disease, disorder or condition related to the dysfunction of the DA neurons of the SN, for a prophylactic or preventive action. Alternatively or additionally, the effective amount may be administered after initiation of a disease, disorder or condition related to the dysfunction of the DA neurons of the SN, for a therapeutic action.
  • Neurologic disorders such as, for example, diseases, disorders or conditions related to the dysfunction of the DA neurons of the SN.
  • neuroprotection may aim at stopping or slowing down the loss of neurons related to these diseases.
  • the present invention relates to a composition
  • a composition comprising a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably an agonist of a receptor expressed by the DA neurons of the SN, and a modulator of the nicotinic cholinergic pathway.
  • depolarizing agents acting on a receptor expressed by the DA neurons of the SN include, but are not limited to, agonists of an orexin receptor (OXR); agonists of a purinergic receptor, preferably of the P2X receptor (P2XR); and agonists of a neurokinin receptor, preferably of the NK1 and/or NK3 receptors.
  • OXR orexin receptor
  • P2XR P2X receptor
  • a neurokinin receptor preferably of the NK1 and/or NK3 receptors.
  • the depolarizing agent is not a K+-channel blocker.
  • Methods for determining if a compound operates as a K+ channel blocker are well- known from the skilled artisan. Examples of such methods include, but are not limited to the demonstration that said compound possesses the molecular/structural requirements for K+ channel blockade; the demonstration by electrophysiological recordings that said compound modifies the activation profile of K+ channels overexpressed in Xenopus oocytes or in mammalian cell lines; the demonstration through binding studies that said compound displaces radioactive forms of known blockers of K+ channels.
  • K+-channel blocker examples include, but are not limited to synthetic compounds such as tetraethylammonium (TEA), and 4-aminopyridine (4- AP) and small peptides such as charybdotoxin (CTX), and apamin (APA).
  • TAA tetraethylammonium
  • 4-AP 4-aminopyridine
  • CTX charybdotoxin
  • APA apamin
  • Methods for determining if a compound is an agonist of a given receptor or receptor/channels are well-known in the art. Examples of such methods include, but are not limited to, the demonstration that well know agonists of the said receptor produce the same biological effect as the test compound using a cell line overexpressing this receptor; the demonstration that known antagonists of the said receptor reduce or prevent the biological effects of the test compound using a cell line overexpressing this receptor.
  • the present invention relates to a composition comprising an agonist of an orexin receptor and a modulator of the nicotinic cholinergic pathway.
  • the agonist of an orexin receptor is an agonist of the 0X1 and/or 0X2 receptor(s). In one embodiment, the agonist of an orexin receptor is a selective agonist of the OX2R.
  • the selectivity for OX2R over OX1R can be assessed by comparing the potency of a given compound to elevate intracellular calcium in stably expressing OX2R and/or OX1R cell lines, such as, for example, PC12 (human pheochromocytoma) or Neuro-2a (murine neuroblastoma) cell lines transfected with cDNA for OX1R and/or OX2R. Examples of methods for measuring intracellular calcium levels include, but are not limited to, Ca 2+ imaging (such as, for example, fura-2 Ca 2+ imaging) (Holmqvist et al, FEBS Lett, 2002).
  • the selective agonist of the OX2R exhibits at least about 10-fold selectivity for OX2R over OX1R, preferably at least about 50-fold selectivity, more preferably at least about 100-fold selectivity for OX2R over OX1R.
  • the agonist of an orexin receptor is an orexin peptide, preferably OXA (human OXA CAS number 205640-90-0), OXB (human OXB CAS number 205640-91-1) or a mixture of OXA and OXB.
  • the agonist of an orexin receptor is OXB.
  • the agonist of an orexin receptor is not a selective agonist of the orexin receptor OX1R.
  • the selective agonist of the orexin receptor OX2R has an affinity for OX2R at least 10-fold, 25-fold, 50-fold, 75-fold, 80-fold, 90-fold, 95 fold, 100-fold, 125-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, preferably 500-fold higher than the affinity for OX1R.
  • the agonist of an orexin receptor is not the OXA peptide.
  • orexin agonists include but are not limited to agonists described in the following patents applications incorporated herein: US2010150840; US2014051700; WO2006081522.
  • the orexin agonist is selected from the list of agonists for type-2 orexin receptor described in US2010/150840 and US2014/051700, such as, for example, compounds of formula:
  • X is CI and Y is CI, or X is CI and Y is H, or X is H and Y is H, or X is OMe and Y is H, or X is H and Y is Br, or X is H and Y is N0 2 ; or compounds of formula:
  • R 1 ; R 2 and R 4 are as described in the Table below: no./salt Rl R2 R4
  • the orexin agonist is selected from the list of orexin agonists described in WO2006/081522 such as orexin A, orexin B, [Ala n ,D-Leu 15 ]-Orexin B.
  • the selective agonist of the orexin receptor OX2R is [Ala u ,D- Leu 15 ]-Orexin B as described in Asahi S et al. Bioorg Med Chem Lett. 2003 Jan 6; 13(l): l l l-3 and in US2004044031 incorporated herein.
  • the present invention relates to a composition
  • a composition comprising an agonist of a purinergic receptor, preferably of the P2X receptor and a modulator of the acetylcholine (ACh) pathway.
  • agonists of the P2X receptor include, but are not limited to, ATP; ATP disodium salt; ATPyS tetralithium salt; ⁇ , ⁇ -Methyleneadenosine 5 '-triphosphate lithium salt; ⁇ , ⁇ -meATP ( ⁇ , ⁇ -methyleneadenosine 5 '-triphosphate trisodium salt); 2- methylthioadenosine triphosphate (2-ME-SATP) tetrasodium salt; 8-Bromoadenosine 5 '-triphosphate sodium salt; BzATP triethylammonium salt; ⁇ , ⁇ -Methyleneadenosine 5'- triphosphate disodium salt; Cytidine 5 '-triphosphate disodium salt; 5-bromouridine 5- triphosphate, 3'-0-(4-benzoylbenzoyl)-ATP, zinc and mixtures thereof.
  • agonists of the P2X receptor include but are not limited to agonists described in the following patents incorporated herein: EP0760850 and WO2007/139775.
  • the P2X receptor agonist is selected from the list of P2X receptor agonists described in EP0760850: ATP, 2meSATP, 2-chloro-ATP, ⁇ , ⁇ -MeATP, ADP, BzATP, AP 5 A, ATP- ⁇ -S, D-1- ⁇ , ⁇ - ⁇ , adenosine, AMP and UTP.
  • the P2X receptor agonist is selected from the list of P2X receptor agonists described in WO2007/139775: N-methanocarba derivatives of AMP, having the following formula:
  • Ri is hydrogen, alkyl, alkoxy, amino, mono- or di-alkylamino, mono or bicyclic cycloalkyl, cycloalkyloxy, aryl, arylalkyl, acyl, sulfonyl, arylsulfonyl, or a mono- or bicyclic thiazolyl group;
  • R 2 is hydrogen, halogen, thiol, cyano, alkyl, alkenyl, alkynyl, alkylthio, alkylsulfmyl, alkylsulfonyl, aryl, arylamino, or aryloxy;
  • R 3 is hydrogen, halogen, methyl, or ethyl; and R 4 and R5 are independently hydrogen, methyl, or methoxy; and in particular the compound MRS2339:
  • the present invention relates to a composition
  • a composition comprising an agonist of a neurokinin receptor (also known as tachykinin receptor), preferably of the NK1 and/or NK3 receptor and a modulator of the nicotinic cholinergic pathway.
  • a neurokinin receptor also known as tachykinin receptor
  • agonists of the NK1 receptor includes, but are not limited to, C14TKL-1; GR 73632; Hemokinin 1 (human); Hemokinin 1 (mouse); [Sar 9 ,Met(0 2 ) n ]-Substance P; substance P; Ranakinin; compounds of the 3-Quinolinecarboxamides family; and mixtures thereof.
  • agonists of the NK3 receptor includes, but are not limited to, Senktide; PG-KII; [MePhe(7)] -neurokinin B ( [MePhe(7 ) ] -NKB ) ; SR142801; and mixtures thereof.
  • the modulator of the nicotinic cholinergic pathway is a modulator of a nAChR, preferably an agonist of a nAChR, even more preferably an agonist of a neuronal nAChR and still even more preferably a modulator of the cc7-nAChR.
  • composition of the invention comprises an orexin peptide, preferably orexin B and NIC.
  • composition of the invention comprises an orexin peptide, preferably orexin B and PNU 282,987.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably an agonist of a receptor expressed by the DA neurons of the SN, and a modulator of the nicotinic cholinergic pathway, and at least one pharmaceutically acceptable excipient.
  • the term "pharmaceutically acceptable excipient” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • the pharmaceutical composition of the invention comprises a composition as hereinabove described.
  • the present invention also relates to a medicament comprising a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably an agonist of a receptor expressed by the DA neurons of the SN, and a modulator of the nicotinic cholinergic pathway.
  • the medicament of the invention comprises a composition as hereinabove described.
  • compositions, pharmaceutical composition or medicament of the invention examples include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphate, acetate, gelatin, collagen, Carbopol®, vegetable oils, and the like.
  • the composition, pharmaceutical composition or medicament of the invention may additionally include suitable preservatives, stabilizers, antioxidants, antimicrobials, and buffering agents, such as, for example, BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
  • compositions, pharmaceutical composition or medicament of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium
  • composition pharmaceutical composition or medicament of the invention may comprise some excipients, such as, for example, surfactants (e.g. hydroxypropylcellulose); suitable carriers, such as, for example, solvents and dispersion media containing, for example, water, ethanol, polyol (e.g.
  • surfactants e.g. hydroxypropylcellulose
  • suitable carriers such as, for example, solvents and dispersion media containing, for example, water, ethanol, polyol (e.g.
  • glycerol, propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils, such as, for example, peanut oil and sesame oil
  • isotonic agents such as, for example, sugars or sodium chloride
  • coating agents such as, for example, lecithin
  • agents delaying absorption such as, for example, aluminum monostearate and gelatin
  • preservatives such as, for example, benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like
  • buffers such as, for example, boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like
  • tonicity agents such as, for example, dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride
  • antioxidants and stabilizers such as, for example, sodium bisulfite,
  • the composition, the pharmaceutical composition or the medicament of the invention is injected, preferably systemically injected.
  • formulations adapted to systemic injections include, but are not limited to, liquid solutions or suspensions, solid forms suitable for solution in, or suspension in, liquid prior to injection.
  • systemic injections include, but are not limited to, intravenous, subcutaneous, intramuscular, intradermal and intraperitoneal injection, and perfusion.
  • the composition for use, the pharmaceutical composition or the medicament of the invention is sterile. Methods for obtaining a sterile pharmaceutical composition include, but are not limited to, GMP synthesis (GMP stands for "Good manufacturing practice").
  • the composition, the pharmaceutical composition or the medicament of the invention is orally administered.
  • formulations adapted to oral administration include, but are not limited to, solid forms, liquid forms and gels.
  • solid forms adapted to oral administration include, but are not limited to, pill, tablet, capsule, soft gelatin capsule, hard gelatin capsule, caplet, compressed tablet, cachet, wafer, sugar-coated pill, sugar coated tablet, orodispersing/orodisintegrating tablet, powder, solid forms suitable for solution in, or suspension in, liquid prior to oral administration and effervescent tablet.
  • liquid form adapted to oral administration include, but are not limited to, solutions, suspensions, drinkable solutions, elixirs, sealed phial, potion, drench, syrup and liquor.
  • administration routes include, but are not limited to, nasal, buccal, rectal, vaginal, topical, intratracheal, endoscopic, transdermal, transmucosal, and percutaneous administration or administration using an aerosol.
  • NIC or PNU 282,987 modulators of the nicotinic cholinergic pathway
  • OXB orexin peptide OXB
  • the depolarizing agent of the composition of the invention and in particular the agonist of the Orexin receptor may have an unmasking effect for neuroprotection mediated by modulators of the nicotinic cholinergic pathway, such as, for example, NIC or PNU 282,987.
  • the present invention thus relates to a composition
  • a composition comprising a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably an agonist of a receptor expressed by the DA neurons of the SN, and a modulator of the nicotinic cholinergic pathway, for, or for use in, neuroprotection.
  • the present invention thus also relates to a composition, a pharmaceutical composition or a medicament as hereinabove described, for, or for use in, neuroprotection.
  • the present invention also relates to a composition comprising a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably an agonist of a receptor expressed by the DA neurons of the SN, and a modulator of the nicotinic cholinergic pathway, for, or for use in, treating a disease, disorder or condition related to the dysfunction of the DA neurons of the SN.
  • the present invention thus also relates to a composition, a pharmaceutical composition or a medicament as hereinabove described, for, or for use in, treating a disease, disorder or condition related to the dysfunction of the DA neurons of the SN.
  • diseases, disorders or conditions related to the dysfunction of the DA neurons of the SN include, but are not limited to, PD or other related neurodegenerative disorders with parkinsonian syndromes, restless legs syndrome, sleep disorders, disorders with deregulations of the sleep-wake cycle, and neuropsychiatric diseases, disorders or conditions.
  • neuropsychiatric diseases, disorders or conditions include, but are not limited to, Alzheimer's disease, attention-deficit/hyperactivity disorder, Tourette's syndrome and schizophrenia.
  • Symptoms of a parkinsonian syndrome may include, without limitation, tremor at rest; akinesia and rigidity, such as, for example, slowness of movements, amimia, micrographia, loss of arm swing, difficulties in walking, sensation of stiffness; joint pain, dystonia, swallowing disorders, abnormal tiredness, trembling sensation, bradykinesia, action tremor, tremors, dysarthria, dysautonomia, dysphagia, dystonia, eye apraxia, limb apraxia, myoclonus, oculomotor tremors, night tremor, gait and posture impairment, sleep disorders...
  • Neurodegenerative disorders with Parkinsonian Syndromes include, but are not limited to, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration or Lewy body dementia.
  • the composition, the pharmaceutical composition or the medicament of the invention is for treating PD or another neurodegenerative disorder with parkinsonian syndromes.
  • the composition, the pharmaceutical composition or the medicament is for treating sleep disorders associated with PD or with another neurodegenerative disorder with parkinsonian syndromes, preferably PD and/or for treating deregulations of the sleep wake cycle associated with PD or with another neurodegenerative disorder with parkinsonian syndromes, preferably with PD.
  • sleep disorders or deregulations of the sleep wake cycle that may be treated by the composition of the invention, in particular sleep disorders associated with PD or with another neurodegenerative disorder with parkinsonian syndromes, preferably PD, include, but are not limited to, daytime sleep attacks, narcolepsy, cataplexy, nocturnal insomnia, REM sleep behavior disorder (RBD), sleep apnea, hallucinations periodic leg movements in sleep (PLMS) and restless legs syndrome, circadian rhythm disorder, hypersomnia.
  • sleep disorders or deregulations of the sleep wake cycle include, but are not limited to, daytime sleep attacks, narcolepsy, cataplexy, nocturnal insomnia, REM sleep behavior disorder (RBD), sleep apnea, hallucinations periodic leg movements in sleep (PLMS) and restless legs syndrome, circadian rhythm disorder, hypersomnia.
  • the sleep disorders or deregulation of the sleep wake cycle that may be treated by the composition of the invention comprises daytime sleep attacks, hallucinations, nocturnal insomnia and REM sleep behavior disorder (RBD).
  • RBD REM sleep behavior disorder
  • sleep disorders or deregulations of the sleep wake cycle do not include insomnia.
  • the sleep disorders or deregulation of the sleep wake cycle that may be treated by the composition of the invention is selected from the list comprising daytime sleep attacks, narcolepsy, cataplexy, REM sleep behavior disorder (RBD), sleep apnea, hallucinations, periodic leg movements in sleep (PLMS) and restless legs syndrome (RLS), circadian rhythm disorder, hypersomnia.
  • the sleep disorders or deregulation of the sleep wake cycle that may be treated by the composition of the invention is selected from the list comprising daytime sleep attacks, hallucinations, and REM sleep behavior disorder (RBD).
  • the composition, the pharmaceutical composition or the medicament of the invention is for preventing the onset of sleep disorders in a PD subject or in a subject affected with another neurodegenerative disorder with parkinsonian syndromes, preferably PD, or for preventing the onset of sleep disorders in a subject at risk of developing PD or another neurodegenerative disorder with parkinsonian syndromes, preferably PD.
  • the composition, the pharmaceutical composition or the medicament of the invention further comprises another therapeutic agent useful for treating PD.
  • therapeutic agents include, but are not limited to dopamine agonists, such as, for example, bromocriptine, cabergoline, pergolide, pramipexole, fenoldopam, ropinirole, rotigotine, quinagolide and apomorphine; monoamine oxidase inhibitors, such as, for example, benmoxin, hydralazine, iproclozide, iproniazid, isocarboxazid, isoniazid, mebanazine, nialamide, octamoxin, phenelzine, pheniprazine, phenoxypropazine, pivalylbenzhydrazine, Pivalylbenzhydrazine, Procarbazine, Safrazine, Caroxazone, Echinopsidine, Furazolidone, Linezolid,
  • the composition, the pharmaceutical composition or the medicament of the invention comprises a therapeutically effective amount of a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, and a therapeutically effective amount of a modulator of the nicotinic cholinergic pathway.
  • the therapeutically effective amount of a depolarizing agent ranges from about 0.01 mg to about 500 mg per kg, preferably from about 0.05 mg to about 100 mg per kg, more preferably from about 0.1 mg to about 10 mg per kg.
  • the therapeutically effective amount of a modulator of the nicotinic cholinergic pathway ranges from about 0.01 mg to about 500 mg per kg, preferably from about 0.05 mg to about 100 mg per kg, more preferably from about 0.1 mg to about 10 mg per kg.
  • the composition, the pharmaceutical composition or the medicament of the invention is administered at least once a month, preferably at least once a week, more preferably at least once a day.
  • the modulator is administered in a sustained- release form.
  • the composition comprises a delivery system that controls the release of the modulator.
  • suitable carriers for sustained or delayed release include, but are not limited to, gelatin; Arabic gum; xanthane polymers; thermoplastic resins such as, for example polyvinyl halides, polyvinyl esters, polyvinylidene halides and halogenated polyolefins; elastomers such as, for example, brasiliensis, polydienes, and halogenated natural and synthetic rubbers; and flexible thermoset resins such as polyurethanes, epoxy resins; biodegradable polymers and the like.
  • the subject is a mammal, preferably a human. In one embodiment of the invention, the subject is a female. In another embodiment of the invention, the subject is a male.
  • the subject is affected, preferably is diagnosed with a disease, disorder or condition related to the dysfunction of the DA neurons of the SN.
  • the subject is at risk of developing a disease, disorder or condition related to the dysfunction of the DA neurons of the SN.
  • risks include, but are not limited to, familial history of disease, disorder or condition related to the dysfunction of the DA neurons of the SN; genetic predisposition to a disease, disorder or condition related to the dysfunction of the DA neurons of the SN; occurrence of REM sleep behavior disorder; exposure to environmental factors and the like.
  • the subject is affected, preferably is diagnosed with PD. In one embodiment, an onset of a symptom of PD has been diagnosed in the subject. In another embodiment, no onset of a symptom of PD has been diagnosed in the subject.
  • symptoms of PD include, but are not limited to, tremor at rest; akinesia and rigidity, such as, for example, slowness of movements, amimia, micrographia, loss of arm swing, difficulties in walking, sensation of stiffness; joint pain, dystonia, swallowing disorders, abnormal tiredness, trembling sensation, bradykinesia, action tremor, tremors, dysarthria, dysautonomia, dysphagia, dystonia, eye apraxia, limb apraxia, myoclonus, oculo-motor tremors, night tremor, gait and posture impairment, sleep disorders and the like.
  • the subject is at risk of developing PD.
  • the subject has a genetic or familial predisposition to PD.
  • the subject presents a non-genetic predisposition to PD.
  • Non-genetic risk factors for developing PD include, but are not limited to, exposure to heavy metals, such as, for example, Lead, Manganese or Copper; exposure to pesticides such as, for example, rotenone or paraquat; exposure to pollutants; exposure to herbicides such as, for example, Substance Orange; exposure to toxic substances, such as, for example, MPTP...
  • the present invention also relates to a method for providing neuroprotection to a subject in need thereof, wherein said method comprises administering to the subject a therapeutically effective amount of a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably of an agonist of a receptor expressed by the DA neurons of the SN, and a therapeutically effective amount of a modulator of the nicotinic cholinergic pathway.
  • the present invention also relates to a method for, or for use in, treating a disease, disorder or condition related to the dysfunction of the DA neurons of the SN to a subject in need thereof, wherein said method comprises administering to the subject a therapeutically effective amount of a depolarizing agent acting on a receptor expressed by the DA neurons of the SN, preferably of an agonist of a receptor expressed by the DA neurons of the SN, and a therapeutically effective amount of a modulator of the nicotinic cholinergic pathway.
  • Figure 1 is a concentration-response curve of the protective effects of OXB for DA neurons.
  • DA tyrosine hydroxylase positive, TH+ neurons at 10 days in vitro (DIV) as a function of OXB concentrations (0.1-10 nM).
  • GDNF was used as positive control at a concentration of 20 ng/ml. Each data point is the mean value of 3 independent experiments. CON: Control.
  • Figure 2 is a bar-graph showing that NIC-mediated protection of DA neurons is unmasked by OXB.
  • the trophic peptide GDNF (20 ng/ml) was used as a reference treatment to protect DA neurons.
  • Each bar is the mean value of 3 independent experiments. Comparisons by one-way ANOVA followed by Student- Newman-Keul
  • FIG. 3 is an illustration that shows the presence of the two orexin receptors OXIR and OX2R in DA neurons in midbrain cultures.
  • Primary antibodies against OXIR and OX2R were revealed using secondary antibodies carrying a green fluorescent dye.
  • White arrows point to DA neurons detected by immunodetection of TH (red fluorescent signal).
  • Insert shows that when OX1R/OX2R antibodies were omitted, no significant green fluorescent signal was detectable in the cultures. Scale bar: 25 ⁇ .
  • Figure 4 is a bar-graph showing the rescuing effects of treatments that combine the OXB peptide with NIC or the cc7 nAChR agonist PNU 282,987. Midbrain cultures were processed for the evaluation of DA cell survival at 10 DIV. OXB was used at 3nM and concentrations of NIC and PNU 282,987 are given in the figure. *P ⁇ 0.05 vs. control. # P ⁇ 0.05 vs. cultures treated with OXB, only. Each bar is the mean value of 4 independent experiments. Comparisons by one-way ANOVA followed by Dunnett's test.
  • Figure 5 is a bar-graph showing that protective effects of OXB are mediated by OX2R.
  • Figure 6 is a bar-graph showing that OXB-mediated protection of dopamine neurons requires activation of intracellular calcium-release channels.
  • 2-APB 2-AminoethoxydiPhenylBorane
  • IP3 receptor antagonist or dantrolene 30 ⁇
  • Figure 7 is a bar-graph showing that OXA provides limited protection to dopamine neurons in comparison to OXB. Counts of dopamine neurons (tyrosine hydroxylase-i-) in midbrain cultures exposed continuously for 10 days to OXB or OXA, each at 10 nM. The effect of OXA was sensitive to the OX2R antagonist EMPA. * p ⁇ 0.05, vs control cultures; # p ⁇ 0.05, vs OXA-treated cultures.
  • Example 1 Survival promoting effects of the composition of the invention
  • Cultures were prepared from the ventral mesencephalon of embryos (gestational age 15.5) harvested from Wistar female rats (Janvier Breeding Center, Le Genest St Isle, France). The protocol for producing and maintaining these cultures has been reported previously in detail (Salthun-Lassalle et al, 2004; Toulorge et al, Faseb J, 2011). The cultures were fed daily by replacing 70% of the medium and pharmacological treatments were applied concurrently. The evaluation of the survival of DA neurons was performed by counting cells immunopositive for TH as described (Toulorge et al, Faseb J, 2011).
  • Figure 1 shows that a chronic exposure to OXB promotes the survival of DA neurons in a concentration-dependent manner. Survival is assessed after 10 days in vitro (DIV). Survival promotion by OXB is compared to that provided by GDNF, a highly potent trophic peptide for DA neurons (Lin et al, Science, 1993). Based on these observations, we tested whether a treatment with the alkaloid NIC could act in synergy with OXB.
  • NIC had no effect by itself but OXB (3 nM) was able to reveal NIC (1 ⁇ M)-mediated protection so that the level of protection provided by a combined treatment with NIC and OXB exceeded that of OXB, alone, demonstrating the presence of a synergy, which is a potentiating effect, between OXB and NIC.
  • a non-specific blocker of acetylcholine nicotinic receptors (nAChRs), mecamylamine (50 ⁇ ) and a specific blocker of brain cc7 nAChRs cc-bungaro toxin ( ⁇ ) prevented the effect of NIC but not that of OXB, confirming the key role played by the cc7 nicotinic receptor subtype in mediating the protective action of the alkaloid (Toulorge et al, Faseb J, 2011).
  • TCS-1102 (1 nM) a dual orexin receptor antagonist prevented the protective effect of OXB and also that of NIC, confirming that the action of the alkaloid relied on that provided by the peptide.
  • Example 2 Characterization of OX receptors in DA neurons
  • OX receptors were carried out in 6-7 DIV midbrain cultures. Briefly, midbrain cultures fixed for 12 min with 4% formaldehyde in PBS were then incubated for 48 h with primary polyclonal antibodies for OX1R (1/100 in PBS; Abeam #ab68718) and OX2R (1/100 in PBS; Abeam #abl04701). The detection of OX1R and OX2R was performed by incubating the cultures for 20 min with an Alexa Fluor-488 conjugate of an anti-rabbit antibody (1/300 in PBS; Molecular Probes).
  • Immunodetection of DA neurons was carried out subsequently with a monoclonal anti- TH antibody (1:5000; Diasorin, Stillwater, MN, USA). Note that immunostainings of OXR were performed in the absence of Triton-X 100, owing to the preferential location of OXR proteins at the plasma membrane level.
  • Figure 3 shows that both receptors are widely expressed by midbrain neurons and more specifically by the subpopulation of DA neurons characterized on the basis of its content in TH.
  • Example 3 Treatments combining the OXB peptide and cc7 nicotinic receptor agonists
  • OXB has the capacity to reveal the protective action of NIC for these neurons (see Example 1).
  • the effect of NIC being mediated by cc7nAChRs we performed complementary studies in order to determine whether OXB had also the potential to reveal protective effects of a specific cc7 nAChR agonist.
  • the present set of data demonstrates that OXB can unmask the protective action of the cc7 nAChR agonist N-(3R)-l-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU 282,987) ( Figure 4).
  • Figure 5 shows that the protective effects of OXB on dopamine neurons are mediated by OX2R.
  • OXB Dopamine neurons in midbrain cultures were exposed continuously for 10 days to OXB (10 nM) in the presence or not of 2-APB (2-AminoethoxydiPhenylBorane, 10 ⁇ ), an IP3 receptor antagonist or dantrolene (30 ⁇ ), a blocker of ryanodine receptor channels.
  • Figure 6 shows that OXB-mediated protection of dopamine neurons requires activation of intracellular calcium-release channels.
  • Dopamine neurons (tyrosine hydroxylase+) in midbrain cultures were exposed continuously for 10 days to OXB or OXA, each at 10 nM.
  • OXA was sensitive to the OX2R antagonist EMPA.
  • FIG. 7 shows that OXA provides limited protection to dopamine neurons in comparison to OXB.

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Abstract

La présente invention concerne une composition comprenant un agent de dépolarisation agissant sur un récepteur exprimé par les neurones dopaminergiques de la substance noire, et un modulateur de la voie cholinergique nicotinique, ledit récepteur exprimé par les neurones dopaminergiques de la substance noire étant un récepteur de l'orexine, un récepteur purinergique ou un récepteur neurokinine ; et son utilisation pour fournir une neuroprotection à un sujet ou pour traiter une maladie, un trouble ou un état associé(e) au dysfonctionnement des neurones dopaminergiques de la substance noire chez un sujet.
PCT/EP2014/057661 2013-04-15 2014-04-15 Agents de dépolarisation et modulateurs du récepteur nicotinique de l'acétylcholine pour le traitement de troubles dopaminergiques WO2014170343A1 (fr)

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US10287305B2 (en) 2016-02-04 2019-05-14 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
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US11319286B2 (en) 2017-08-03 2022-05-03 Takeda Pharmaceutical Company Limited Heterocyclic compound and application thereof
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US11292766B2 (en) 2016-02-04 2022-04-05 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
US10508083B2 (en) 2016-02-04 2019-12-17 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
US10898737B2 (en) 2016-02-04 2021-01-26 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
US10287305B2 (en) 2016-02-04 2019-05-14 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
US11034700B2 (en) 2017-03-08 2021-06-15 Takeda Pharmaceutical Company Limited Substituted pyrrolidine compound and use thereof
US11059780B2 (en) 2017-03-08 2021-07-13 Takeda Pharmaceutical Company Limited Substituted pyrrolidine compound and use thereof
WO2018232282A1 (fr) * 2017-06-15 2018-12-20 Board Of Regents, The University Of Texas System Procédés et plates-formes de filtrage et de sélection de métabolites et de leurs récepteurs
US11746374B2 (en) 2017-06-15 2023-09-05 Board Of Regents, The University Of Texas System Methods and platform for screening and selecting metabolites and their receptors
US10584097B2 (en) 2017-08-03 2020-03-10 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US11319286B2 (en) 2017-08-03 2022-05-03 Takeda Pharmaceutical Company Limited Heterocyclic compound and application thereof
US11440883B2 (en) 2017-08-03 2022-09-13 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US10428023B2 (en) 2017-08-03 2019-10-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US11655241B2 (en) 2018-06-29 2023-05-23 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US11028048B2 (en) 2019-01-31 2021-06-08 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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