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WO2017205610A1 - Utilisation d'agonistes de récepteurs de l'angiotensine ii dans le traitement et la prévention d'accidents vasculaires cérébraux - Google Patents

Utilisation d'agonistes de récepteurs de l'angiotensine ii dans le traitement et la prévention d'accidents vasculaires cérébraux Download PDF

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Publication number
WO2017205610A1
WO2017205610A1 PCT/US2017/034450 US2017034450W WO2017205610A1 WO 2017205610 A1 WO2017205610 A1 WO 2017205610A1 US 2017034450 W US2017034450 W US 2017034450W WO 2017205610 A1 WO2017205610 A1 WO 2017205610A1
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Prior art keywords
receptor agonist
stroke
pharmaceutically acceptable
solvate
acceptable salt
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Colin Sumners
Douglas M. BENNION
Ulrike M. STECKELINGS
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Institute Of Molecular Medicine University Of Southern Denmark
University of Florida
University of Florida Research Foundation Inc
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Institute Of Molecular Medicine University Of Southern Denmark
University of Florida
University of Florida Research Foundation Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to the use of compounds that are angiotensin II receptor agonists, more particularly selective agonists of the angiotensin II type 2 receptor (hereinafter the AT2 receptor), and especially agonists that bind selectively to that receptor, for treating or preventing stroke.
  • the angiotensin II receptor agonists are administered w ' a the intranasal trans-olfactory route.
  • a stroke is an acute neurological disorder caused when there is a disturbance in blood circulation to or within the brain, which results in brain cell damage or death. It is a leading cause of death and disability in the United States and worldwide.
  • ischemic stroke wherein the blood supply to part of the brain is decreased
  • haemorrhagic stroke in which bleeding occurs in or around the brain. Stroke can result in dysfunction or death of the brain tissue in the affected area, which can in turn result in the sufferer experiencing impaired walking, talking, speech, balance, co-ordination, vision, spatial awareness, swallowing, bladder and bowel control, and in severe instances, death.
  • An ischemic stroke is the most common form of stroke, accounting for approximately 85% of instances.
  • An ischemic stroke is caused by a blockage of the blood vessels of the brain, usually by the formation of a blood clot within the brain, or when a blood clot, which has been transported through the circulatory system, becomes lodged in the brain.
  • a blockage restricts the blood flow to the affected area of the brain, and results in a lack of oxygen in the cells in the affected area.
  • a lack of oxygen quickly results in necrosis of the affected cells in the core area of the stroke.
  • brain cells within the area surrounding the core known as the penumbra, are also exposed to ischemia and many of them die within days to weeks via a process of cell death known as apoptosis.
  • transient ischemic attack A temporary interruption of the supply of blood to the brain is known as a transient ischemic attack (TIA), or "mini-stroke".
  • TIA transient ischemic attack
  • mini-stroke A temporary interruption of the supply of blood to the brain is known as a transient ischemic attack (TIA), or "mini-stroke”.
  • TIA transient ischemic attack
  • mini-stroke A temporary interruption of the supply of blood to the brain is known as a transient ischemic attack (TIA), or "mini-stroke”.
  • TIA transient ischemic attack
  • mini-stroke mini-stroke
  • Haemorrhagic stroke is caused by bleeding inside (intracerebral haemorrhage) or around (subarachnoid haemorrhage) the brain.
  • the blood accumulates and compresses the surrounding brain tissue, resulting in damage to the cells and tissue of the affected region.
  • Causes of intracerebral hemorrhage include hypertension, trauma, infections, tumors, blood clotting deficiencies, and abnormalities in blood vessels.
  • Causes of subarachnoid haemorrhage include cerebral aneurysms, trauma, blood clotting deficiencies and arteriovenous malformation.
  • tPA tissue plasminogen activator
  • Dysphagia occurs in up to 65% of patients who have suffered a stroke. This reduces patient compliance for drugs formulated for oral administration. In addition, oral administration of drugs during the initial medical evaluation of stroke patients is contraindicated for many patients who may be candidates for surgical interventions.
  • Angiotensin II is a hormone of the RAS which has the ability to interact with different receptors to provoke a range of physiological processes.
  • the angiotensin II type 1 receptor is the most abundant of the Ang II receptors and is responsible for most of the physiological and pathological processes associated with Ang II.
  • the AT2 receptor is expressed less in adult tissue but is up-regulated in pathological conditions, including stroke.
  • AT2 receptor stimulation has been shown to promote anti-inflammatory, anti-proliferative and vasodilatory effects (Guimond et al., Int. J. Hypertens., 2012:351758; Gallo-Payet et al., Front Endocrinol., 201 1 , 2:17; Rompe et al., Hypertension. 2010;55(4):924-31 ).
  • mice lacking angiotensin II type 2 receptors exhibit a larger infarct size post ischemic stroke (Iwai et al. Circulation, 2004; 1 10, 843- 848).
  • AT2 receptor agonists either peptides or non-peptides, have been shown to elicit neuroprotection in rodent models of ischemic stroke.
  • the inventors have now found a new method of treating or preventing stroke which addresses some of the deficiencies of the prior art.
  • a method of treating or preventing stroke comprises intranasal trans-olfactory (INTO) administration of up to 0.75 ⁇ g/kg bodyweight of an angiotensin II receptor agonist (e.g. an AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, wherein the patient is human.
  • INTO intranasal trans-olfactory
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • a pharmaceutically acceptable salt or solvate thereof e.g. an AT2 receptor agonist
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of stroke in a human patient wherein up to 0.75 ⁇ g/kg bodyweight of the angiotensin II receptor agonist (e.g. the AT2 receptor agonist) is administered via the intranasal trans-olfactory route to a patient in need thereof.
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of stroke in a human patient wherein up to 0.75 ⁇ g/kg bodyweight of the AT2 receptor agonist (e.g. the AT2 receptor agonist) is administered via the intranasal trans-olfactory route to a patient in need thereof.
  • ischemic stroke is possible with intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) administration of an AT2 receptor agonist
  • these routes of administration are often ineffective or impractical for use in human subjects who are suffering from an ischemic stroke, or a transient ischemic attack. This is particularly so in patients who have difficulty in swallowing (e.g. patients suffering from dysphagia) or who are candidates for surgical interventions.
  • the methods and uses described herein are those wherein the patient is exhibiting dysphagia (swallowing difficulties).
  • a method of treating or preventing stroke comprises intranasal trans-olfactory (INTO) administration of an angiotensin II receptor agonist (e.g. an AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, wherein the patient is human.
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • an angiotensin II receptor agonist e.g.
  • an AT2 receptor agonist for use in the treatment or prevention of stroke in a human patient wherein the AT2 receptor agonist (e.g. the AT2 receptor agonist) is administered via the intranasal trans-olfactory route to a patient in need thereof.
  • the AT2 receptor agonist e.g. the AT2 receptor agonist
  • a drug delivery device suitable e.g., having the capacity, designed, configured, capable of) for intranasal trans-olfactory (INTO) administration
  • a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (e.g., a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier, for use in the treatment or prevention of stroke in a human patient.
  • the device delivers up to 0.75 g kg (or other dosage delineated herein) of the AT2 receptor agonist via intranasal trans-olfactory administration to a patient in need thereof,
  • the device comprises instructions or labeling for use of the device to administer its contents to a patient for use in the treatment or prevention of stroke.
  • a container comprising a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound capable of stimulating AT2 receptors (e.g., a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof), in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier; and
  • kits instructions or labeling for use of the formulation in the treatment or prevention of stroke in a human patient, wherein the kit is suitable for intranasal trans-olfactory administration of the formulation to a human patient.
  • the device delivers up to 0.75 ⁇ g/kg (or other dosage delineated herein) of the AT2 receptor agonist via intranasal trans-olfactory administration to a patient in need thereof.
  • intranasal trans-olfactory administration is non-invasive, and very easy to perform.
  • administration via the intranasal trans-olfactory route may be accomplished by a first aider or an untrained person, and so may not require the need for a medically trained professional.
  • Most available AT2 receptor agonists are peptides which are unable to cross the blood brain barrier, making these unsuitable treatments for i.p. administration in humans.
  • One such peptide is CGP421 12A, as noted above. Successful use of i.p.
  • the inventors have surprisingly found that compounds that are angiotensin I I agonists, and more particularly agonists of the angiotensin I I type 2 receptor (the AT2 receptor), and especially agonists that bind selectively to that receptor, are of use in the treatment and/or prevention of stroke when the AT2 receptor agonist is administered via intranasal trans-olfactory delivery.
  • the inventors have found that intranasal trans-olfactory administration of certain doses (including 1 .5 ⁇ g/kg bodyweight) of the AT2 receptor agonist to rats delivers similar, if not improved, neuroprotective effects when compared to a higher i.p.
  • compositions that are useful in the methods of the invention may be administered at varying doses.
  • suitable doses i.e. therapeutically effective doses
  • suitable doses i.e. therapeutically effective doses
  • suitable doses are in the range of from about 0.01 to about 0.75 bodyweight (e.g. 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 , 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75 g/kg bodyweight or any range or value therein).
  • More preferred doses are in the range of from about 0.03 to about 0.55 ⁇ g/kg bodyweight.
  • More preferred doses are in the range of from about 0.05 to about 0.5 ⁇ g/kg bodyweight. More preferred doses are in the range of from about 0.1 to about 0.5 ⁇ g/kg bodyweight.
  • references herein to dosage units in the form of " g/kg", or similar, are references to dosages in units of g kg bodyweight of the subject to be treated.
  • Particularly preferred doses of compounds that are useful in the methods of the invention may be from about 0.1 to about 0.3 ⁇ g/kg bodyweight.
  • Compounds that are useful in the methods of the invention may be administered over multiple (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 and the like) doses to the patient over a fixed period of time wherein the total dose is up to about 0.75 ⁇ g/kg.
  • the AT2 receptor agonist, or pharmaceutically acceptable salt or solvate thereof is administered over a plurality of doses.
  • the AT2 receptor agonist, or pharmaceutically acceptable salt or solvate thereof is administered over up to 4 (e.g. 1 , 2, 3, 4) doses.
  • the AT2 receptor agonist, or pharmaceutically acceptable salt or solvate thereof is administered over 1 or 2 doses.
  • the AT2 receptor agonist or pharmaceutically acceptable salt or solvate thereof, is administered via a single dose (e.g. no more than one dose over in one day, or no more than one dose over in one week, or no more than one dose following any given occurrence of a stroke).
  • the compounds that are useful in the methods of the invention may be administered more than once over a defined period of time.
  • the in vivo half-life of a compound may be such that multiple dosing over a single day is required in order to maintain a sufficient level of the compound, or active metabolite thereof, in vivo.
  • the compounds that are useful in the methods of the invention may be administered up to 10 times per day, preferably up to 6 times per day (e.g. up to 4 times per day).
  • the AT2 receptor agonist may be administered over a period of several months as part of ongoing treatment of a subject who has suffered a stroke. During this time, the subject may be administered the AT2 receptor agonist at a frequency that is appropriate to maintain a sufficient level of the compound, or active metabolite thereof, in vivo, for example at any of the frequencies mentioned here.
  • the physician or the skilled person, will be able to determine the actual dosage (including frequency) which will be most suitable for an individual subject, which is likely to vary with the condition that is to be treated, as well as the age, weight, sex and response of the particular subject to be treated.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the AT2 receptor agonist is administered as rapidly as possible following the occurrence of a stroke.
  • Ongoing treatment of a subject who has suffered a stroke may occur for periods including, but not limited, to one week, one month, or in certain instances, for an unlimited duration following the stroke.
  • the AT2 receptor agonist may be administered for preventative use to a subject who is considered to be at risk of stroke. Preventative use may include daily dosing for up to an unlimited duration.
  • the AT2 receptor agonist, or pharmaceutically acceptable salt or solvate thereof is administered in the form of a powder, or particularly a solution or suspension comprising said AT2 receptor agonist or salt or solvate thereof.
  • compounds used in the methods of the invention are agonists of the AT2 receptor. More particularly, compounds used in the methods of the invention may be selective agonists of the AT2 receptor.
  • terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
  • references to "one or more" of a particular component or integer will be understood to refer to from one to a plurality (e.g. two, three or four) of such components or integers. It will be understood that references to "one or more" of a particular component or integer will include a particular reference to one such integer.
  • prevention By the term “prevent”, “preventing”, or “prevention of” (and grammatical variations thereof) it is meant that the likelihood of the patient suffering from the condition is reduced, at least partially reduced or averted and/or that some prophylaxis, or inhibition of at least one clinical symptom is achieved and/or there is a delay in the onset of the disease or disorder. Prevention, in this respect, also includes reducing the likelihood of a second or further occurrence of a stroke in an individual that has already suffered a first such event.
  • stroke refers to an acute cerebrovascular, neurological disorder caused when there is a disturbance in blood circulation to or within the brain, which results in brain cell damage or death in that area.
  • the symptoms of stroke include partial or complete hemiplegia, central facial palsy, dysphagia, sudden severe headache, dizziness, loss of balance and coordination, blurred vision, confusion, difficulty talking and loss of consciousness. It is possible for a stroke not to result in any outward symptoms, this is described as being a "silent stroke”. Any stroke can result in dysfunction or death of the brain tissue in the affected area, which can in turn result in the sufferer experiencing impaired walking, talking, speech, balance, co-ordination, vision, spatial awareness, swallowing, bladder and bowel control, and in severe instances, death.
  • stroke can be classified into two major categories: ischemic and haemorrhagic.
  • An ischemic stroke occurs when the blood supply to part of the brain is decreased, leading to a lack of oxygen in the cells in the affected area. In turn, a lack of oxygen quickly results in necrosis of the affected cells in the core area of the stroke.
  • brain cells within the area surrounding the core known as the penumbra, are also exposed to ischemia and many of them die within days to weeks via a process of cell death known as apoptosis.
  • the decreased blood supply may be due to, or at least in part due to, but not limited to thrombosis, an embolism, systemic hypoperfusion or cerebral venous sinus thrombosis.
  • An ischemic stroke may be cryptogenic in nature, wherein the cause is unknown. Ischemic strokes account for approximately 85% of instances of stroke.
  • a transient ischemic attack (TIA), or "mini-stroke" is similar to an ischemic stroke but the blood supply to the brain is only temporarily interrupted and gives rise to the same symptoms as a stroke. However, the symptoms resolve themselves within 24 hours. Patients having suffered a transient ischemic attack are considered to be at risk of a full ischemic stroke.
  • Ischemic strokes can be classified according to several known systems.
  • OCSP Oxford Community Stroke Project classification
  • a stroke can be classified as a total anterior circulation infarct, a partial anterior circulation infarct, a lacunar infarct or a posterior circulation infarct.
  • TOAST Trial of Org 10172 in Acute Stroke Treatment
  • a stroke can be classified as being due to thrombosis, embolism due to atherosclerosis, an embolism originating in the heart, a complete blockage of a small blood vessel, another determined cause, or an undetermined cause.
  • Haemorrhagic stroke occurs when a blood vessel within the skull bursts and bleeds inside (intracerebral haemorrhage) or around (subarachnoid haemorrhage) the brain. The accumulation of the blood compresses and damages the surrounding brain tissue and cells. Haemorrhagic stroke leads to a lack of oxygen in the cells in the affected area. In turn, a lack of oxygen quickly results in necrosis of the affected cells in the core area of the stroke.
  • causes of intracerebral haemorrhage include hypertension, trauma, infection, tumours, blood clotting deficiencies, and abnormalities in blood vessels.
  • causes of subarachnoid haemorrhage include cerebral aneurysms, trauma, blood clotting deficiencies and arteriovenous malformation.
  • the risk factors associated with stroke include, but are not limited to, age, sex, high blood pressure, atrial fibrillation, smoking (active and passive), obesity, high cholesterol, sickle cell disease, carotid artery disease, peripheral artery disease, diabetes, lack of exercise, poor diet, alcohol abuse, drug abuse and atrial-septal defect.
  • an AT2 receptor agonist can be achieved via a variety of routes (e.g. by i.c.v. or i.p. as discussed above).
  • the inventors believe that intranasal trans-olfactory (INTO) administration, whereby 50-100% of the formulated drug is deposited on the surface of the tissue of the olfactory region, gives improved delivery to the intracerebral area of stroke compared to other routes of administration.
  • Intranasal trans-olfactory administration typically occurs over a period of a few seconds (e.g. 1 to 2 seconds) and is an alternative to intranasal administration.
  • INTO facilitates non-invasive drug delivery to the brain by delivering a drug directly to the olfactory region. This allows significant quantities of the drug to pass through the olfactory system as a whole and enter the brain via the olfactory bulb.
  • the olfactory region contains bipolar neurons within the olfactory epithelium. These bipolar neurons have ends that may be accessible by drugs. These bipolar neurons also congregate to form the olfactory nerves. These nerves pass through the cribriform plate to the olfactory bulb, the neural structure of the forebrain involved in the sense of smell. In this way, the blood brain barrier might be circumvented and drugs which are suitable for treating neurological disorders, but are unsuitable to systemic administration because they are not able to cross the blood brain barrier, may potentially be able to enter the brain..
  • a drug In order to achieve meaningful nose-to-brain delivery, significant quantities of a drug must be deposited to the olfactory region.
  • Devices that are suitable for this use include inter alia the precision olfactory delivery nasal device developed by Impel NeuroPharma and the Optinose AS OptimistTM device (Vasa et al., 2015). Due to the complex architecture of the upper nasal cavity, traditional nasal delivery (as opposed to intranasal trans-olfactory delivery) typically deposits a very small amount of a drug (e.g. less than 5%) to the olfactory region, and therefore does not allow for significant levels of nose-to- brain delivery.
  • Methods of the invention can involve the use of AT2 receptor agonists that fully or partially stimulate or activate the AT2 receptor.
  • the AT2 receptor agonist is a compound that can stimulate or activate the AT2 receptor.
  • the methods of the invention involve the use of an AT2 receptor specific agonist that binds selectively to the AT2 receptor.
  • the compounds discussed herein may also bind to the angiotensin II type 1 receptor (hereinafter the AT1 receptor), and may be agonists or antagonists of that receptor.
  • the AT1 receptor is expressed in most organs, and is believed to be responsible for the majority of the biological effects of angiotensin II.
  • the AT2 receptor is more prevalent than the AT1 receptor in foetal tissues, the adult ovaries, the adrenal medulla and the pancreas. An equal distribution is reported in the brain and uterus (Ardaillou, J. Am. Soc. Nephrol., 10, S30-39 (1999)).
  • Preferred compounds for use in the methods of the invention are those that bind selectively to the AT2 receptor.
  • the affinity ratio for the relevant compound is at least 50:1 , for example, at least 100:1 , preferably at least 1000:1 , more preferably at least 4000:1 , more preferably at least 10000:1 , and even more preferably at least 25000:1 .
  • the AT2 receptor agonist is an AT2 receptor agonist that stimulates an AT2 receptor (e.g. a selective AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof.
  • the term "concomitant administration” or “combination administration” or the like of a compound, therapeutic agent or known drug with an AT2 receptor agonist as defined herein means administration of a known medication or drug to a subject and, in addition, the administration of one or more AT2 receptor agonists as defined herein to the same subject at such time that both the known drug and the compound will have a therapeutic effect. In some cases this therapeutic effect will be synergistic.
  • Such concomitant administration can involve concurrent (i.e. at the same time), prior, or subsequent administration of the known drug with respect to the administration of an AT2 receptor agonist as defined herein.
  • a person skilled in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and AT2 receptor agonists.
  • Compounds of the invention may be administered either alone or in combination with other agents that are known in the art to be useful in the treatment of stroke, such as recombinant tissue plasminogen activators (e.g. Activase®). Such combinations may therefore be useful in the therapeutic treatment of stroke.
  • the AT2 receptor agonist, or pharmaceutically acceptable salt or solvate thereof is administered in combination with a recombinant tissue plasminogen activator, or a pharmaceutically acceptable salt or solvate thereof.
  • the AT2 receptor agonist and the recombinant tissue plasminogen activator may be administered concomitantly, separately or sequentially.
  • an AT2 receptor agonist may be administered to a patient that has already received or is already receiving treatment with a recombinant tissue plasminogen activator.
  • a method of treating or preventing stroke in a human patient comprises intranasal trans-olfactory administration of up to 0.75 g kg bodyweight of an angiotensin II receptor agonist (e.g. an AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof, wherein the patient has already received or is already receiving treatment with a recombinant tissue plasminogen activator.
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • a pharmaceutically acceptable salt or solvate thereof e.g. an AT2 receptor agonist
  • the recombinant tissue plasminogen activator may be administered to a patient that has already received or is already receiving treatment with an AT2 receptor agonist.
  • a method of treating or preventing stroke in a human patient comprises administration of a recombinant tissue plasminogen activator to a patient in need thereof, wherein the patient has already received or is already receiving treatment with up to 0.75 g kg bodyweight of an angiotensin II receptor agonist (e.g. an AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof, via intranasal trans-olfactory administration.
  • an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • Compounds of the invention may also be administered in combination with other AT2 agonists that are known in the art, as well as in combination with AT1 receptor antagonists that are known in the art, and/or in combination with an inhibitor of angiotensin converting enzyme (ACE).
  • ACE angiotensin converting enzyme
  • Non-limiting but illustrative examples of AT1 receptor antagonists that can be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan and/or combinations thereof.
  • Non-limiting but illustrative examples of ACE inhibitors that can be used according to the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and/or combinations thereof. Such combinations may therefore be useful in the therapeutic treatment of stroke through the use of the methods disclosed herein.
  • a combination product comprising:
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of stroke in a human patient, wherein up to 0.75 ⁇ g/kg of the AT2 receptor agonist is administered via intranasal trans-olfactory administration to a patient in need thereof.
  • Such combination products provide for the administration of an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (as defined herein), in conjunction with an AT1 receptor antagonist and/or an ACE inhibitor, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises an AT2 receptor agonist or a compound that stimulates an AT2 receptor (as defined herein), and at least one formulation comprises an AT1 receptor antagonist and/or an ACE inhibitor, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation including an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor together with either an AT1 receptor antagonist or an ACE inhibitor, or both an AT1 receptor antagonist and an ACE inhibitor).
  • a combined preparation i.e., presented as a single formulation including an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor together with either an AT1 receptor antagonist or an ACE inhibitor, or both an AT1 receptor antagonist and an ACE
  • a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (e.g., a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof) and an AT1 receptor antagonist and/or an ACE inhibitor in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier, for use in the treatment or prevention of stroke in a human patient, wherein up to 0.75 g kg of the AT2 receptor agonist is administered via intranasal trans- olfactory administration to a patient in need thereof; and
  • a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound capable of stimulating AT2 receptors (e.g., a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof), in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier; and
  • components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, for use in the treatment or prevention of stroke in a human patient, wherein up to 0.75 ⁇ g/kg of the AT2 receptor agonist is administered via intranasal trans-olfactory administration to a patient in need thereof.
  • salts include, but are not limited to, acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents (as required) of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo or by freeze-drying).
  • Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • pharmaceutically acceptable derivatives of compounds useful in the methods of the invention are included within the scope of the invention (e.g. solvates etc.).
  • pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and arylsulphonic acids; and from metals such as sodium, magnesium, potassium and calcium.
  • the pharmaceutically acceptable salt is a Na salt (i.e. a sodium salt of an AT2 receptor agonist), or an HCI salt (i.e. an HCI salt of an AT2 receptor agonist).
  • Compounds that are useful in the methods of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
  • a particular compound that that may be mentioned as being useful in the methods of the invention is N-butyloxycarbonyl-3-(4-imidazol-1 -ylmethylphenyl)-5-iso-butylthiophene-2- sulfonamide (also known as C21 ), or a pharmaceutically acceptable salt or solvate thereof.
  • the angiotensin II receptor agonist e.g. the AT2 receptor or other compound that stimulates an AT2 receptor, such as a selective AT2 receptor agonist
  • the AT2 receptor or other compound that stimulates an AT2 receptor is N-butyloxycarbonyl-3-(4-imidazol- 1 -ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide, or a pharmaceutically acceptable salt or solvate thereof.
  • a particular pharmaceutically acceptable salt of a compound useful in the methods of the invention that may be mentioned includes the HCI salt.
  • a further particular pharmaceutically acceptable salt of a compound useful in the methods of the invention that may be mentioned includes the sodium salt.
  • the angiotensin II receptor agonist e.g. the AT2 receptor agonist or other compound that stimulates an AT2 receptor, such as a selective AT2 receptor agonist
  • the compound N-butyloxycarbonyl-3-(4-imidazol-1 - ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (C21 ), with the structure provided in Figure 1 may be made in accordance with techniques well known to those skilled in the art; for example, as described in international patent application WO 2002/096883, the contents of which are hereby incorporated by reference. In the case of a discrepancy between the name of the compound and the structure provided in Figure 1 , the structure provided in Figure 1 should prevail.
  • the skilled person will understand that all embodiments of the invention as described herein may be combined with one or more other embodiments of the invention. Further, the embodiments described in one aspect of the present invention are not limited to the aspect described. The embodiments may also be applied to a different aspect of the invention as long as the embodiments do not prevent these aspects of the invention from operating for its intended purpose.
  • a "patient in need" of the methods of the invention can be a subject known to have suffered or suspected of having suffered a stroke, e.g. wherein the stroke is an ischemic stroke or a haemorrhagic stroke.
  • the stroke is an ischemic stroke.
  • the angiotensin II receptor agonist will normally be administered via intranasal trans-olfactory administration in a pharmaceutically acceptable dosage form.
  • references to a "patient” to be treated may be synonymous with a "subject”, and vice versa.
  • the compounds that are useful in the methods of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including sprays, solutions, suspensions and powders. Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Suitable excipients include those commonly used for nasal delivery, e.g. normal saline.
  • a pharmaceutical formulation comprising an angiotensin II receptor agonist (e.g. an AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof, wherein the formulation comprises between 0.7 and 50 ⁇ g of the angiotensin II receptor agonist (e.g. the AT2 receptor agonist), or pharmaceutically acceptable salt or solvate thereof.
  • Said pharmaceutical formulations may be used to treat or prevent stroke in a human.
  • the pharmaceutical formulation comprising an angiotensin II receptor agonist (e.g. an AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof comprises between 5 and 25 ⁇ g of the angiotensin II receptor agonist (e.g.
  • the pharmaceutical formulation comprising an angiotensin II receptor agonist comprises about 17 ⁇ g of the angiotensin II receptor agonist (e.g. the AT2 receptor agonist), or pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical formulation comprising an angiotensin II receptor agonist e.g. an AT2 receptor agonist
  • a pharmaceutically acceptable salt or solvate thereof may be administered to the patient in need thereof one or more times.
  • the pharmaceutical formulation is administered on one or two occasions following the occurrence of a stroke.
  • angiotensin II receptor agonist e.g. the AT2 receptor agonist
  • the angiotensin II receptor agonist is N-butyloxycarbonyl-3-(4-imidazol-1 -ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide or a pharmaceutically acceptable salt thereof.
  • the angiotensin II receptor agonist comprised in the pharmaceutical formulation is an AT2 receptor agonist or other compound that stimulates an AT2 receptor (e.g. a selective AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical formulation comprises between 0.7 and 50 ⁇ g, preferably between 5 and 25 ⁇ g, and most preferably about 17 ⁇ g of the angiotensin II receptor agonist (e.g. the AT2 receptor agonist), or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of stroke.
  • angiotensin II receptor agonist e.g. the AT2 receptor agonist
  • a pharmaceutically acceptable salt or solvate thereof in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of stroke.
  • references to preceding and following periods of time will refer to periods of time preceding or following the time of treatment (or intended treatment) with compounds that are useful in the methods of the invention.
  • the methods of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, enable easier absorption than, and/or provide a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological properties than methods known in the prior art. Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer.
  • a rat dose can be converted to an estimated human equivalent dose by multiplying the rat dose by 0.16 (or dividing by 6.2). This conversion factor is in line with that published by FDA (see Guidance for Industry, 2005, page 7, Table 1 ). Therefore a 1 .5 g kg dose in a rat corresponds to a 0.24 ⁇ g/kg equivalent dose in a human.
  • Figure 1 The structure of N-butyloxycarbonyl-3-(4-imidazol-1 -ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21 ).
  • the figure illustrates ET-1 induced middle cerebral artery occlusion (MCAO), measuring cerebral blood flow as % of baseline. As illustrated there is a decrease in cerebral blood flow after ET-1 injection.
  • MCAO middle cerebral artery occlusion
  • Post-stroke delivery of INTO (intranasal trans-olfactory) C21 decreases cerebral infarct volume.
  • Percent cerebral infarct size is expressed as a percent of the ipsilateral hemisphere infarction as compared to the healthy contralateral hemisphere. ** p ⁇ 0.05 versus saline control by.
  • FIG. 4 Neuroprotective actions of intranasal trans-olfactory (INTO) C21 against ET-1 ischemic stroke in young adult SD rats - Neurological scores - Post-stroke delivery of INTO C21 improves neurological function.
  • Naive normotensive rats were implanted in the abdominal aorta with Data Sciences International (St. Paul, MN, USA) pressure telemetry transducers, under isoflurane anesthesia. Following 1 week of recovery, transducers were tested for patency, and baseline blood pressure (mean arterial pressure; MAP), heart rate and locomotor activity measurements were made. Rats then began a crossover study, with half of the cohort receiving 0.9% saline ( ⁇ /
  • ) and the other half receiving C21 ( T/ ⁇ , 30 ⁇ /kg), i.p., followed by recordings of MAP, heart rate and locomotor activity for 4 hours. Two days later, the treatments were reversed, followed again by the above recordings. N 8 rats total. Data are mean ⁇ SEM.
  • FIG. 1 0 is the calculated/graphed data, showing C21 levels in the RIGHT olfactory.
  • FIG. 12 is the calculated/graphed data, showing C21 levels in plasma. Associated with the graph is the actual data, and a calculation of the concentration (nM) in each situation.
  • C21 -Stroke 773 ⁇ 1 14 pg/mL ( ⁇ 1 .57 nM).
  • C21 -Naive 1217 ⁇ 222 pg/mL ( ⁇ 2.48 nM).
  • FIG. 13 is the calculated/graphed data, showing C21 levels in the RIGHT
  • FIG. 14 is the calculated/graphed data, showing C21 levels in the striatum. Associated with the graph is the actual data, and a calculation of the concentration (nM) in each situation.
  • C21 -Stroke (pg/g): 635, 447, 771 , 1040. Mean 723 ⁇ 124 pg/g - 1 .45 nM.
  • Mean 94 ⁇ 29 pg/g - 0.19 nM.
  • FIG. 15 is the calculated/graphed data, showing C21 levels in plasma. Associated with the graph is the actual data, and a calculation of the concentration (nM) in each situation.
  • C21 -Stroke (pg/mL): 32503; 61213; 55196; 91305. Mean 60,054 ⁇ 121 13 pg/mL - 120.68 nM.
  • C21 -Naive (pg/mL): 26700; 27961 ; 19836; 45913. Mean 30,103 ⁇ 5564 pg/mL ⁇ 60.4 nM. Materials and Methods Stock solution of C21
  • C21 as a stock powder (in the form of a sodium salt of C21 ) was dissolved in 0.9% sterile saline to make fresh solution for each experiment, and solutions were kept on ice until immediately before INTO delivery.
  • Endothelin-1 (ET-l )-induced middle cerebral artery occlusion (MCAO).
  • mice were anaesthetized with a mixture of 0 2 (1 .5 L min -1 ) and 4% isoflurane and placed in a Kopf stereotaxic frame, and anaesthesia was maintained for the duration of surgery using an 0 2 -isoflurane (2%) mixture delivered through a nose-cone attached to the frame.
  • Animals then underwent an intracranial operation essentially as detailed previously (Bennion DM, Haltigan EA, Irwin AJ, Donnangelo LL, Regenhardt RW, Pioquinto DJ, Purich DL, Sumners C (2015). Activation of the Neuroprotective angiotensin-converting enzyme 2 in rat ischemic stroke.
  • CBF was measured by Laser Doppler Flowmetry using a Standard Pencil Probe (placed just posterior to the MCAO burr hole) and a Blood Flow Meter coupled to a Powerlab 4/30 with LabChart 7 (ADInstruments, Inc., Colorado Springs, CO).
  • an analgesic agent was administered to the rat (buprenorphine; 0.05 mg kg -1 S.C; Hospira Inc., Lake Forest, IL, USA) before waking.
  • an analgesic agent was administered to the rat (buprenorphine; 0.05 mg kg -1 S.C; Hospira Inc., Lake Forest, IL, USA) before waking.
  • IP injections to attain an effective neuroprotective dose of 0.03 mg/kg (30 ⁇ g kg), adjusted the volume injected depending on the size of the rat. For example: inject 0.3 mL of 30 ⁇ g mL IP for a 300 g rat.
  • an effective neuroprotective dose is 1 .5 ⁇ g/kg.
  • adjusted the volume depending on the size of the rat. For example: deliver 15 ⁇ _ of the 30 ⁇ g/mL solution IN into a 300 g rat. (15 ⁇ _ contains 0.45 ⁇ g of C21 ; 0.45 ⁇ g 300g rat 1 .5 ⁇ g/kg)
  • FIG. 2 illustrates the animal stroke model utilized in the study.
  • the method of Endothelin-1 induced stroke has been described in detail in the articles Mecca et al., Exp. Physiol. (201 1 ), 96:1084-1096; Joseph et al., Neuropharmacology 2014; 81 :134- 141 , and in brief in the methods and materials above.
  • the figure illustrates ET-1 induced middle cerebral artery occlusion (MCAO), measuring cerebral blood flow as % of baseline. As illustrated there is a decrease in cerebral blood flow after ET-1 injection.
  • Figures 3 and 4 show the neuroprotective actions regarding infarct size and neurological scores following intranasal trans-olfactory administration of C21 .
  • Figure 3 illustrates the neuroprotective actions of intranasal trans-olfactory administration of C21 against ET-1 ischemic stroke in young adult SD rats with regards to infarct size.
  • the data shows that post-stroke delivery of C21 using intranasal trans-olfactory administration decreases cerebral infarct volume.
  • Intranasal trans-olfactory C21 delivery at 1 .5 ⁇ g/kg but not at 30 ⁇ g/kg (nor at 6.25 Mg/kg), effectively decreases ischemic stroke-induced neurological deficits.
  • Figure 4 illustrates that post-stroke delivery of intranasal trans-olfactory C21 improves neurological function using Bederson and Garcia exams.
  • Figure 5 shows a comparison of effects of C21 by route of administration (i.c.v. (intracerebroventricular), i.p. (intraperitoneal) and intranasal trans-olfactory routes of C21 administration against ET-1 ischemic stroke in young adult SD rats.
  • Treatments with C21 in stroke has previously been shown to be neuroprotective by i.c.v. and i.p. administration.
  • Figure 5 shows that post-stroke infusion of intranasal trans-olfactory C21 induces similar if not improved neuroprotective effects compared to i.c.v. and i.p. administration.
  • the actual amount of C21 required to produce comparable therapeutic effect via INTO delivery is 20 x less than that required via i.p. delivery.
  • the solution used to obtain 1 .5 g kg intranasal trans-olfactory was the same concentration as the solution used to obtain 30 g/kg i.p. Administration of 300 ⁇ via the i.p. route was performed, but only 15 ⁇ intranasal trans-olfactory (20 x less) per a 300g rat.
  • Blood pressure should be maintained, not lowered, under stroke conditions, because it is important that circulation to the affected brain area (particularly the stroke penumbra) is maintained. Therefore, it is desirable that drugs that are beneficial in stroke do not lower blood pressure.
  • Previous studies have indicated that i.p.-administered C21 does not normally alter blood pressure. However, studies have indicated that long-term (2 to 4 weeks) intracerebroventricular infusion of C21 lowers blood pressure in normal and hypertensive rats (Gao Jet al., Am. J. Hypertens.. 201 1 ;24:724-30; Brouwers S, et al., Clin. Sci. (Lond.). 2015;129:81 -92.).
  • Figures 6 - 8 illustrate that intranasal trans- olfactory administration or i.p. administration of C21 does not alter blood pressure, heart rate or activity of na ' ive normotensive rats.
  • Figure 6 illustrates intranasal trans-olfactory administration of C21 (neuroprotective dose) and
  • Figure 7 illustrates intranasal trans- olfactory C21 (30 g kg i.p. -equivalent dose).
  • Figure 8 illustrates i.p. administration of C21 (neuroprotective dose, 30 g/kg).
  • Figure 9 illustrates that intranasal trans-olfactory administration of C21 (neuroprotective dose) does not alter blood pressure, heart rate or activity of normotensive rats during acute ET-1 -induced ischemic stroke.
  • C21 in the serum after INTO administration ( ⁇ 2nM). While not entirely clear how it gets there, one possibility is penetration through the nasal mucosa and uptake into the circulation by capillaries. Regardless, it does not appear that the C21 seen in the cortex, striatum and olfactory is derived from the blood, for the above- mentioned reasons. Additionally, a further indication that intranasally applied C21 really reaches the brain via the INTO route and not via the circulation is that after INTO application, C21 levels in the olfactory bulb (which is within the BBB) are higher than in plasma. If C21 would reach the brain via the circulation and diffuse from the blood into the tissue, the reverse would be expected.

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Abstract

L'invention concerne une nouvelle utilisation de composés qui sont des agonistes de récepteurs de l'angiotensine II, plus particulièrement des agonistes sélectifs du récepteur de type 2 de l'angiotensine II (récepteur AT2), et en particulier des agonistes qui se lient sélectivement à ce récepteur, pour le traitement ou la prévention d'accidents vasculaires cérébraux, ledit agoniste des récepteurs de l'angiotensine II étant administré via la voie trans-olfactive intranasale.
PCT/US2017/034450 2016-05-25 2017-05-25 Utilisation d'agonistes de récepteurs de l'angiotensine ii dans le traitement et la prévention d'accidents vasculaires cérébraux Ceased WO2017205610A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006915A1 (fr) * 2002-07-11 2004-01-22 Universite De Picardie Jules Verne Agents stimulateurs des recepteurs non at1 de l'angiotensine destines a prevenir l'ischemie cerebrale et a traiter l'accident vasculaire cerebral aigu
US20040167176A1 (en) * 2001-05-31 2004-08-26 Mathias Alterman Tricyclic compounds useful as angiotensin II agonists
US20120035232A1 (en) * 2010-06-11 2012-02-09 Vicore Pharma Ab Use of angiotensin ii agonists
US20140014104A1 (en) * 2011-03-03 2014-01-16 Impel Neuropharma Inc. Nasal Drug Delivery Device

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040167176A1 (en) * 2001-05-31 2004-08-26 Mathias Alterman Tricyclic compounds useful as angiotensin II agonists
WO2004006915A1 (fr) * 2002-07-11 2004-01-22 Universite De Picardie Jules Verne Agents stimulateurs des recepteurs non at1 de l'angiotensine destines a prevenir l'ischemie cerebrale et a traiter l'accident vasculaire cerebral aigu
US20120035232A1 (en) * 2010-06-11 2012-02-09 Vicore Pharma Ab Use of angiotensin ii agonists
US20140014104A1 (en) * 2011-03-03 2014-01-16 Impel Neuropharma Inc. Nasal Drug Delivery Device

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