WO2020069934A1 - Composition neuroprotectrice - Google Patents

Composition neuroprotectrice

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Publication number
WO2020069934A1
WO2020069934A1 PCT/EP2019/075826 EP2019075826W WO2020069934A1 WO 2020069934 A1 WO2020069934 A1 WO 2020069934A1 EP 2019075826 W EP2019075826 W EP 2019075826W WO 2020069934 A1 WO2020069934 A1 WO 2020069934A1
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WIPO (PCT)
Prior art keywords
myelin
composition
nmda
antagonist
concentrations
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Application number
PCT/EP2019/075826
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English (en)
Inventor
Robert Fern
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University Of Plymouth
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Publication of WO2020069934A1 publication Critical patent/WO2020069934A1/fr

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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

Definitions

  • the central nervous system is made up of grey matter (GM), where the neuron cell bodies are located and form synapses with other neurons, and white matter (WM), where the long projections (axons) of these neurons run.
  • GM grey matter
  • WM white matter
  • WM The function of WM is the transmission of signals to, from and between neurons and this requires the presence of insulation on many of the long axonal neuronal projection called axons.
  • the insulation is provided by layers of myelin that wrap around the axons, and the myelin is generated by a cell type called the oligodendrocyte.
  • MR.I imaging reveals white matter myelin damage in many diseases.
  • disorders that are effectively caused by“pure” white matter damage such as but not limited to spinal cord injury (SCI), cerebral palsy (CP), vascular dementia (VaD), multiple sclerosis (MS), traumatic brain injury (TBI), ischemic optic neuropathy (ION) and certain kinds of stroke. Damage to myelin in these diseases has serious consequences; for example MS is a product of pure myelin damage.
  • neurological diseases affect grey matter but have an important white matter component, including but not limited to Alzheimer’s, Huntingdon’s and Parkinson’s diseases, depression, schizophrenia and some forms of stroke.
  • An aspect of the present invention provides a composition for protecting against demyelination and other forms of myelin injury, comprising a combination of an NDMA-type glutamate receptor antagonist and a non-NMDA-type glutamate receptor antagonist.
  • the concentration of each antagonist may be at a level below a clinically effective uncombined level.
  • the concentrations of both antagonists may be at least one order of magnitude lower than the clinically effective levels.
  • the concentration of both antagonists may be at least two orders of magnitude lower than the individually effective levels.
  • each antagonist may be at a level below an in vacuo sub-clinically effective level. In other words, both concentrations are at a level below that which would normally be expected for either drug to be clinically effective when administered individually.
  • the NMDA receptor blocker memantine is typically prescribed at 20 mg/day and the non-NMDA receptor blocker parampanel is typically prescribed at 4-8 mg/day (current UK NICE guidelines).
  • a 2 mg/day memantine and 0.4-0.8 mg/day parampanel dose may, for example, be prescribed in combination.
  • concentrations of both antagonists may be at least one order of magnitude lower than said in vacuo sub-clinically effective levels.
  • the concentrations of both antagonists may be at least two or more orders of magnitude lower than said in vacuo sub-clinically effective levels.
  • Some aspects and embodiments of the present invention are based on a principle of a low-combined dose.
  • a further aspect relates to the combined use of low concentrations of any NMDA and any non-NMDA antagonist. This is based on data showing that the clinically approved drugs Parampanel (AMPA blocker) + memantine (NMDA blocker) are protective in vitro at very low combined concentrations.
  • AMPA blocker clinically approved drugs Parampanel
  • NMDA blocker memantine
  • a further aspect relates to the combined use of a selective GluN2C/D NMDA receptor blocker in combination with any non-NMDA blocker, at any concentration range. This is based on data showing that QNZ-46+CP465022 are highly protective at low combined doses in two in vivo models (EAE model of multiple sclerosis and tMCAO model of stroke).
  • Some aspects and embodiments relate to the use of low concentrations of any NMDA and non-NMDA antagonist in combination at low concentrations.
  • a further aspect provides the use of the combination of a NDMA-type glutamate receptor antagonist and a non-NMDA glutamate receptor antagonist for protecting against demyelination.
  • a further aspect provides the use of a combined non-NMDA glutamate receptor and GluN2C/D subunit containing NMDA glutamate receptor antagonist for the prophylaxis and/or treatment of neurological disease.
  • a further aspect provides the use of a composition comprising an NMDA blocker selected from Table I in combination with an AMPA blocker selected from Table I for the protection of myelin.
  • Uses described herein may be for the treatment or prophylaxis of neurological disease.
  • Some aspects and embodiments of the present invention relate to a combined non-NMDA glutamate receptor and a GluN2C/D subunit-containing NMDA glutamate receptor antagonism for protection and treatment of neurological disease, in particular those affecting myelin.
  • the GluN2C/D subunit-containing NMDA glutamate receptor antagonist may comprise QNZ-46 or a functional equivalent thereof.
  • QNZ-46 is a selective, negative allosteric modulator of NMDA receptors that contain a GluN2C/D subunit:
  • the GluN2C/D subunit-containing NMDA glutamate receptor antagonist may consist of QNZ-46.
  • the non-NMDA antagonist may comprise an AMPA receptor blocker.
  • the non-NMDA antagonist may comprise CP465022 or a functional equivalent thereof.
  • CP465022 is a selective non-competitive antagonist of the AMPA non-NMDA receptor.
  • the non-NMDA antagonist may consist of CP465022.
  • the present invention also provides a neuroprotective composition comprising a selective non-NMDA receptor blocker in combination with a selective GluN2C/D containing receptor blocker. Both blockers may be present at the clinically effective level required when either is delivered individually. Both blockers may be present at concentrations below a clinically effective level required when either is delivered individually/separately.
  • the present invention also provides a composition for the protection of myelin comprising an NMDA blocker selected from Table I in combination with an AMPA blocker selected from Table I .
  • Both blockers may be present at in vacuo sub-clinically effective concentrations.
  • the antagonists may be present at established clinically effective concentrations.
  • the present invention also provides the use of a formulation as described herein for the treatment of a neurological disease.
  • the present invention also provides the use of a formulation as described herein for the treatment of multiple sclerosis.
  • the present invention also provides the use of a formulation as described herein for the prevention of demyelination.
  • a further aspect provides a method of treating or preventing myelin injury by administering to a person in need of such treatment an effective amount of a composition as described herein.
  • a further aspect provides use of a composition as described herein in the treatment or prophylaxis of myelin damage.
  • a further aspect provides use of a composition described herein in the treatment or prophylaxis of disorders or diseases of the nervous system involving myelin pathology including but not limited to: spinal cord injury, cerebral palsy, vascular dementia, multiple sclerosis, traumatic brain injury, ischemic optic neuropathy and stroke.
  • neurological diseases that involve significant myelin damage to which the present invention may be applicable include but are not limited to: Alzheimer’s, Huntingdon’s and Parkinson’s diseases, depression, schizophrenia and disorders affecting the peripheral nervous system (such as diabetic neuropathy), the neurological complications of AIDS, prion diseases, metabolic disorders, genetic disorders and toxicities affecting myelin.
  • a further aspect relates to use of combined non-NMDA glutamate receptor and GluN2C/D subunit containing NMDA glutamate receptor antagonist for the protection and/or treatment of neurological disease.
  • a further aspect relates to use of combined AMPA antagonist and GluN2C/D subunit containing NMDA glutamate receptor antagonist for the protection and/or treatment of neurological disease.
  • Many diseases include myelin damage, and we include herein data from the in vivo tMCAO model of stroke using combined low doses that show protection of areas that are not white matter.
  • the present invention also relates to uses described herein for the protection and/or treatment of non-white matter injury in stroke.
  • the present invention also provides an ex vivo system for testing the protective effect of drugs against demyelination, comprising the administration of cuprizone in the present of a putative protective drug.
  • the present invention also provides an ex vivo system for producing selective myelin loss in a sample, for example comprising exposing the sample to cuprizone, LPS or other myelin damaging environment.
  • This embodiment may form the basis for testing drugs that may be protective against myelin damage in vivo or clinically.
  • the system may comprise means for visualising myelin or otherwise measuring the functional integrity of myelin.
  • the present invention also provides a system comprising a means for visualising myelin based upon QNZ- 46 or similar structures.
  • the present invention also provides a system comprising a means for visualising myelin based upon QNZ- 46 or a functionally or a structurally equivalent thereof.
  • An important recent discovery in myelin research is the presence of functional NMDA-type glutamate receptors (GluRs), reported to be expressed at densities comparable to those found at neuronal synapses ' , 2 .
  • GluRs NMDA-type glutamate receptors
  • These myelinic NMDA receptors may play a role in the control of myelin development 3 and the uptake of energy substrate 4 , and we and others have shown that they can be over-stimulated under pathological conditions leading to myelin injury and associated loss of axonal function 5 ' 6 .
  • Myelin also contains AMPA-type non-NMDA GluRs 7 , which can also mediate cytotoxic injury 8 ' 9 . Since AMPA receptors can act to gate NMDA receptor currents, these two receptors may act synergistically in a putative myelinic excitotoxic pathway.
  • Multiple sclerosis is a debilitating neuroinflamatory disorder targeting the axon myelin sheath, the insulating, low capacitance layer required for fast action potential propagation.
  • NMDA receptors are significant in multiple sclerosis demyelination
  • normal appearing white matter (NAWM), active lesion (AL) and chronic lesion (CL) tissue from 3 donors was embedded, ultra-sectioned and immune-gold post-stained for the GluN I obligatory NMDA receptor subunit using protocols previously developed for post-embedded immune-electron microscopy (l-TEM) in rodent tissue for this antibody l 2, l 3 , and human tissue using a similar protocol l4 , in my laboratory.
  • l-TEM post-embedded immune-electron microscopy
  • FIG. 1 GluN I reactivity in multiple sclerosis (NMDA-type GluR expression).
  • E-H Active lesion (AL) regions contain areas of sever myelin decompaction and splitting (arrow heads) which are often associated with focal points of intense GluN I reactivity (arrows in boxed areas are shown at higher gain). Reactivity can also be seen in non-myelin areas surrounding axons which may be the remnants of glial processes (H“gp”).
  • H“gp” The proportion of myelin occupying the tissue in low- power images, showing the significant myelin loss in lesion sites.
  • J Immuno-gold particle density in the three regions broken down for whole sections, myelin and non-myelin staining. Note the significant increases in myelin reactivity in CL and AL tissue compared to NAWM. Scale bars as shown.
  • OGD oxygen-glucose deprivation
  • Drug lipid solubility was found to be a requirement for effective myelin protection by NMDA blockers, consistent with the expression of GluRs within the myelin sheath ' 2 .
  • the drug QNZ-46 is a 4-oxo- 3(4H)quinazolinyl derivative containing the trans-stilbene pharmacophore that targets mylein 20 and a quinazolinone backbone which exhibits strong fluorescence 21 .
  • Quinazolinone derivatives such as QNZ- 46 have a wide range of clinical uses and have a good safety record (see 22 ).
  • the drug has a peak emission at 450 nm allowing drug uptake into myelin to be monitored in real time.
  • Quinazolinone such as QNZ-46 are ideally suited to avoid these problem for the following reasons: I ) High lipid-solubility allows rapid myelin access 6 . 2) Drugability with good brain penetration 6 . 3) Trans-stilbene pharmacore providing unique myelin trapping 6 . 4) Negative allosteric mode of action and use-dependent block, predisposing the drug to target pathological over-activation of receptors over normal physiological receptor function 20 2S . 5) Selective for GluN2C/D containing NMDA receptors which are primarily extra-synaptic 26-28 and are expressed at low levels in grey matter regions than are other NMDA GluR subunits 29, 3 °, consistent with limited on-target side effects.
  • CP465022 (3-(2-Chlorophenyl)-2-[2-[6-[(diethylamino)methyl]-2-pyridinyl]ethenyl]-6-fluoro-4(3H)- quinazolinone) is a highly selective and potent non-competitive quinazolinone antagonist of AMPA type non-NMDA GluRs 3 I . Delivered alone, this drug failed to provide protection in a rodent in vivo model of stroke 32 . As a close analogue of QNZ-46, CP465022 is likely to share the characteristics of myelin penetration and retention of its fellow quinazolinone.
  • Non-NMDA GluRs It is a feature of non-NMDA GluRs that they act to gate NMDA GluRs and we here show that both QNZ-46 and CP465022 protect myelin from injury in a model of acute demyelination.
  • the two drugs are shown to provide protection at low concentrations. When applied together at concentrations below those required to provide protection when applied individually, the drugs provide protection when applied in combination. This synergistic effect of the two drugs acting in combination reduces the concentrations required for protection by ⁇ 2 orders of magnitude and are in the nM range.
  • Figure 2 An ex-vivo cuprizone model of demyelination, showing the protocol which involves hemi- secting live mouse brain slices and staining the myelin with a vital dye such as FluoroMyelin Red. The two halves of each section are then exposed to cuprizone for 100 min, with one side simultaneously exposed either to a drug or a vehicle control. The level of myelin retained by the slice is then assessed via an assay such as a confocal fluorescent microscopy.
  • a vital dye such as FluoroMyelin Red
  • Figure 3 The advantages of the ex-vivo cuprizone model. Current models for testing drugs against myelin damage (top) require large numbers of animals to be monitored over long periods. The new approach described here generates multiple data from a single animal in a single day, with a higher level of statistical power.
  • Figure 4. Data from the ex-vivo cuprizone model. A: Myelin in the corpus callosum of mouse brain slices is shown stained red. The myelin stain is lower in the slice that has been exposed for 100 min to cuprizone (CPZ) compared to one that has not been exposed (control). The level of myelin staining in 6 pairs of slices is shown to the right showing the significant myelin loss produced by cuprizone exposure.
  • CPZ cuprizone
  • FIG. 1 Ultra-micrograph TEM analysis showing pattern of myelin damage in axons of the corpus callosum fixed after 100 min cuprizone treatment.
  • A The significant reduction in axon g-ratio following cuprizone treatment over the range of axon diameters, indicative of myelin disruption.
  • B Representative myelinated axons in the optic nerve and brain slice. Note the similarities to the myelin disruption seen following cuprizone treatment to those in MS patients in Figure I .
  • This new model is ideal for dose-protection work to identify the concentrations at which drugs protect myelin from injury.
  • the model can be adapted to use other conditions that may be relevant to myelin damage.
  • LPS bacterial endotoxin lipopolysaccharide
  • the new assay shows that combined low-doses of NMDA + AMPA antagonists (both experimental and clinically approved) are protective of myelin injury.
  • Figure 7 The dose-dependence of the protective effect of QNZ-46 against ex vivo cuprizone induced myelin loss assessed via FluoroMyelin Red staining.
  • the stated concentrations of the drug are added 60 min before and continually during the 100 min period of cuprizone treatment.
  • the fold difference in myelin protection is calculated relative to myelin staining in the second hemi-section in absence of the drug.
  • I I the increasing protection with increasing drug concentration.
  • the data point in red is the degree of protection produced by a combined treatment with 500 nM QNZ-46 + 10 nM CP465022.
  • Figure 8 The dose-dependence of the protective effect of CP465022 against ex vivo cuprizone induced myelin loss assessed via FluoroMyelin Red staining (as in Figure 7).
  • the data point in red is the degree of protection produced by a combined treatment with 500 nM QNZ-46 + 10 nM CP465022.
  • Figure 9 The protective effect of CP465022 and QNZ-46 against ex vivo cuprizone induced loss of the CAP in the isolate MON.
  • B The time-course of the mean CAP loss when cuprizone is perfused over the tissue (orange), and the protective effect of combined I mM QNZ 46 and I mM CP 465022 (yellow).
  • C Representative CAP from these experiments.
  • Figure 10 The dose-dependence of the protective effect of memantine against ex vivo cuprizone induced myelin loss assessed via FluoroMyelin Red staining (as in Figure 7).
  • the data point in red is the degree of protection produced by a combined treatment with 200 nM memantine + 200 nM parampanel.
  • Figure I I The dose-dependence of the protective effect of parampanel against ex vivo cuprizone induced myelin loss assessed via FluoroMyelin Red staining (as in Figure 7). The data point in red is the degree of protection produced by a combined treatment with 200 nM memantine + 200 nM parampanel. The protective effect of memantine and parampanel was confirmed by CAP recording ( Figure 12). In this assay cuprizone injury was prevented by simultaneous perfusion with I mM memantine and I mM parampanel and these concentrations had no significant protective effect when applied in isolation.
  • the novel combined low-dose therapy identified using the new in vitro assay translates to established in vivo models.
  • a dose of 5 +2 mg/Kg has previously been used in a standard transient middle-cerebral artery occlusion (tMCAO) model of stroke without any protective effect 32 .
  • 20 mg/Kg QNZ-46 has been previously used as an effective dose to reduced ischemic injury in vivo with no behavioural effects, and has been modelled to produce a CSF concentration appropriate for block of myelinic GluN2C/D-containing NMDA receptors 6 .
  • a combined daily dose of I mg/Kg CP465022 + 2 mg/Kg QNZ-46 given via intraperitoneal injection (IP) is therefore ⁇ one order of magnitude lower than the doses required for each drug in isolation in vivo. It must be recognized that the 4 Hr half-life will result in a much lower circulating concentration for the majority of a 24hr dosing regimen.
  • the low combined dose was delivered daily (vs., vehicle) in an established in vivo mouse model of demyelination (experimental autoimmune encephalopathy: EAE).
  • EAE effective autoimmune encephalopathy
  • Experiments were conducted blind and the drug-treated group had a significantly lower area under the curve (AUC) of neurological injury score and a latter latency to onset, and therefore the treatment showed significant efficacy (Figure 13).
  • AUC area under the curve
  • Figure 13 The EAE model is widely used for testing of drugs for multiple sclerosis.
  • FIG. 14 Low combined dose treatment (I mg/Kg CP465022 + 2 mg/Kg QNZ-46) significantly protected against tMCAO injury.
  • Left Three brain sections are shown vertically arranged, collected form mice subject to tMCAO (60 min) + 24 hr recovery and stained for TCC (the white area indicates the damaged part of the brain). Treatment was delivered 120 min prior to the onset of the tMCAO.
  • the table shows data from individual mice and is collated in the two histograms. These stow the significant reduction in lesion volume (as a % of the brain volume) and the reduced Bederson score, which is indicated of functional improvement.
  • FIG. 1 Low combined dose treatment (I mg/Kg CP465022 + 2 mg/Kg QNZ-46) significantly protected against tMCAO injury to myelin.
  • Salter MG Fern R. Nmda receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005;438: l 167- 1 171
  • Lipton SA Failures and successes of nmda receptor antagonists: Molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults.
  • NeuroRx the journal of the American Society for Experimental NeuroTherapeutics. 2004; 1 : 101 - 1 10
  • Nr2b and nr2d subunits coassemble in cerebellar golgi cells to form a distinct nmda receptor subtype restricted to extrasynaptic sites.
  • the Journal of neuroscience the official journal of the Society for Neuroscience. 2003;23:4958-4966

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Abstract

L'invention concerne une composition pour la protection contre la démyélinisation et d'autres formes de lésion de la myéline, comprenant une combinaison d'un antagoniste de récepteur de glutamate de type NDMA et d'un antagoniste de récepteur de glutamate de type non NMDA.
PCT/EP2019/075826 2018-10-05 2019-09-25 Composition neuroprotectrice WO2020069934A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2023144163A1 (fr) 2022-01-25 2023-08-03 Albert-Ludwigs-Universität Freiburg Inhibiteur de glun2d destiné à être utilisé le traitement ou la prévention de la rechute d'un épisode dépressif

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