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WO2022167778A1 - Ebselen en tant que modulateur du récepteur de l'adénosine - Google Patents

Ebselen en tant que modulateur du récepteur de l'adénosine Download PDF

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Publication number
WO2022167778A1
WO2022167778A1 PCT/GB2022/000014 GB2022000014W WO2022167778A1 WO 2022167778 A1 WO2022167778 A1 WO 2022167778A1 GB 2022000014 W GB2022000014 W GB 2022000014W WO 2022167778 A1 WO2022167778 A1 WO 2022167778A1
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disease
compound
condition
ebselen
receptor
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Vijay Kumar PABBATHI
Sriharsha KANTAMNENI
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Haiku Therapeutics Ltd
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Haiku Therapeutics Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to modulation of the adenosine A2A receptor, and in particular to the compound Ebselen as a modulator of the adenosine A2A receptor.
  • Adenosine receptors belong to the superfamily of G protein-coupled receptors (GPCRs). GPCRs constitute one of the primary signal transduction systems in eukaryotic cells and target for numerous clinically used medicines. An overview of their characteristic structural features, molecular interactions, cellular functions, and their roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases, is given by Borea et. al., in Physiol Rev 98: 1591-1625, 2018, May 30, 2018; doi:10.1152/physrev.00049.2017.
  • the adenosine A2A receptor is one of four adenosine receptors and, through coupling to G-proteins, stimulates adenylate cyclase (AC) and increases cyclic adenosine monophosphate (cAMP) levels. They play a role in many diseases including cardiovascular diseases, autoimmune diseases, neurodegenerative and psychiatric diseases, cancers, and inflammatory diseases.
  • A2A receptor modulators agonists and antagonists have been indicated in the treatment of a variety of diseases and conditions, such as described below.
  • Bleeding disorders include haemophilia, von Willebrand disease, coagulation disorders, platelet disorders and clotting factor deficiencies. They affect the way the body controls blood clotting. Treatment generally involves medicines or clotting factor replacement therapy.
  • US 2014/0271606 discloses methods for treating bleeding disorders, in particular, haemophilia, with A2A receptor antagonists.
  • Administration of a A2A receptor antagonist was shown to reduce blood loss in subjects with Haemophilia A and Haemophilia B, demonstrating pro-haemostatic properties of A2A receptor antagonists.
  • This document further discloses methods including administration of an A2A receptor antagonist with one for more of Factor VIII, Factor IX, and Factor XI.
  • Bleeding disorders and obstetric complications are discussed by Gernsheimer, in ‘Congenital and acquired bleeding disorders in pregnancy’, Hematology Am Soc Hematol Educ Program (2016) 2016 (1): 232-235, with particular reference to von Willebrand disease, coagulation factor deficiencies, and inherited disorders of platelet number or function.
  • Endometriosis is a chronic inflammatory condition in which tissue similar to the lining of the womb starts to grow in other places, such as in the ovaries and fallopian tubes. It can cause chronic pelvic pain, dysmenorrhea, period pain, pain during or after sex, premature birth, difficulty in conceiving, and in some cases, it can lead to infertility. Treatments include the use of painkillers, hormone medicine and contraceptives, and surgery.
  • W02012137012 indicates the involvement of the A2A receptor in endometrial cancer.
  • US 5877180 discloses a method of treating inflammatory disorders with A2A receptor agonists, and specifically recites the treatment of infertility from endometriosis.
  • W02003000694 indicates the use of A2A receptor antagonists in the treatment of spontaneous infertility.
  • A2A antagonists are known to relieve pain.
  • Vincenzi et. al. in ‘Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain’, (Review) antagonists relief of pain due to inflammation and peripheral neuropathy.
  • Luongo et. al. in Targeting metabotropic adenosine receptors for neuropathic pain: Focus on A2A’, Brain, Behavior, and Immunity, 69, 10, 1016/j.bbi, 2018.02.014, discuss A2AR selective blockade in decreasing surgical pain and A2AR inhibition in reducing neuropathic pain.
  • WO 2003063876 discloses A2A receptor antagonists in the treatment of movement disorders such as Parkinson’s disease.
  • US 5,484,920 describes compounds having a xanthine skeleton, and A2A receptor antagonist activity, as therapeutic agents for Parkinson’s disease.
  • W02004019949 discloses A2A receptor antagonists in the treatment of restless legs syndrome.
  • A2A receptor antagonists for the treatment of extra-pyramidal syndrome and other movement disorders, such as periodic leg movement in sleep, are described in US20060106040.
  • Adenosine near the tumor microenvironment binds to the A2ARs on immune cells, activating the A2A signalling pathway and inactivating immune response function (Merighi et al., Targeting A3 and A2A adenosine receptors in the fight against cancer, Expert Opin Ther Targets, 2019 Aug, 23(8):669-678).
  • inhibiting A2A receptors could offer a potential treatment strategy to promote immune response and thus supporting cancer therapy, for example as checkpoint inhibitors in such therapy, either alone or in combination with other therapeutic agents.
  • W02009015236 discloses the compound 4-hydroxy-4- methyl-piperidine- 1 - carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide, an A2A receptor antagonist, in the treatment of post-traumatic stress disorder.
  • W02006009698 describes the amelioration of addictive behaviour through the administration of an A2A receptor antagonist.
  • W02004108137 describes a method of treating an anxiety disorder selected from the group consisting of panic disorder, agoraphobia, obsessive-compulsive disorder, social phobia, post- traumatic stress disorder, and specific phobia, through administration of an A2A receptor antagonist.
  • WO9628163 discloses A2A receptor agonists for use increasing the contractile performance of a compromised myocardium in a mammal.
  • WO201 1133696 relates to the use of A2A receptor antagonists for the treatment or inhibition of atherosclerotic lesions.
  • the A2A receptor also plays a role in wound healing.
  • A2A receptor stimulation has been found to promote wound healing, while inhibition of this target prevents/reduces dermal scarring (Jiang and Rinkevich, Int J Mol Sci. 2020 Jan 17;21 (2):617).
  • Other experimental evidence suggests that inhibition of A2AR diminishes scarring while improving the healed wound's collagen composition and tensile strength (Perez-Aso et. al., FASEB J. 2012 Oct; 26(10):4254-63. doi: 10.1096/fj.12-209627. Epub 2012 Jul 5.).
  • A2A receptors are distributed in blood vessels and they mediate vasodilation, suggesting that activation of A2A receptor agonists can dilate blood vessels, particularly in clinical situations such as ischemic cardiac damage.
  • WO9857651 discloses that selective stimulation of adenosine A2A receptors can reduce or prevent restenosis following revascularisation procedures.
  • Revascularisation procedures may be performed on, for example, coronary arteries, renal arteries, leg arteries and carotid arteries, and can include, for example, any of balloon angioplasty, insertion of a stent, insertion of a bypass graft, directional coronary atherectomy, percutaneous transluminal coronary angioplasty and excimer laser angioplasty.
  • A2A receptors are known to play a role in the treatment of autoimmune diseases, as evidenced for example in Chhabra et. al., ‘The immunosuppressive role of adenosine A2A receptors in ischemia reperfusion injury and islet transplantation’, Curr Diabetes Rev. 2012 Nov;8(6):419-33 and Sun et. al., ‘In Vivo Positron Emission Tomography Imaging of Adenosine A2A Receptors’ Front Pharmacol, 2020 Nov 26;11 :599857.
  • Autoimmune diseases of interest include, for example, Hashimoto’s thyroiditis, Guillain-Barre syndrome, and pemphigus.
  • W02003000694 indicates the use of A2A receptor antagonists in the treatment of both Hashimoto’s thyroiditis and pemphigus.
  • CNS Disorders
  • WO 2011057199 discloses methods for treating CNS disorders including methods for increasing the blood brain barrier permeability in a subject through the administration of A1 and A2A receptor agonists.
  • WO 2012137012 cites (paragraph bridging pages 38 and 39) heart failure (such as acute decompensated heart failure and congestive heart failure); kidney failure (e.g. caused by heart failure); oedema; cancer (such as prostate, rectal, renal, ovarian, endometrial, thyroid, pancreatic, particularly breast, colon, bladder, brain, glia, melanoma, pineal gland and, more particularly, lung cancer (e.g. Lewis lung carcinoma)); diabetes; diarrhea; macular degeneration (such as macular degeneration caused by angiogenesis (e.g. retinal angiogenesis)); or, particularly (e.g.
  • a disease of the central nervous system such as depression, a cognitive function disease, a neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; an attention related disorder (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extra pyramidal syndrome (e.g. dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); a disorder of abnormal movement (such as restless leg syndrome (RLS) and periodic limb movement in sleep (PLMS)); cirrhosis; liver fibrosis; fatty liver; dermal fibrosis (e.g. in diseases such as scleroderma); a sleep disorder; stroke; brain injury and neuroinflammation (e.g. migraine or any disorder or condition caused by ischemia, stroke, head injury or CNS inflammation); and addictive behaviour.
  • ADD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • extra pyramidal syndrome e.g. dys
  • Adenosine for myocardial perfusion and Istradefylline (8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1 ,3-diethyl-7-methylpurine- 2, 6-dione) for the treatment of Parkinson’s disease, as an adjunct to levodopa and carbidopa.
  • Istradefylline 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1 ,3-diethyl-7-methylpurine- 2, 6-dione
  • Ebselen (CAS Registry Number 60940-34-3), 2-Phenyl-1 ,2-benzisoselenazol- 3(2/-/)-one, is an organoselenium compound with the following structure:
  • Ebselen mimics glutathione peroxidase activity, catalysing several reactions to protect cellular components from oxidative and free radical damage. It is classed an antioxidant, an anti-inflammatory agent, a cyclooxygenase inhibitor, a neuroprotective agent, and an anti-ulcer agent.
  • Ebselen is, or has been, the subject of clinical trials for a number of indications, including for use in patients with Covid-19, patients with Meniere’s Disease, and patients with Cystic Fibrosis.
  • Ebselen, 2-Phenyl-1 ,2- benzisoselenazol-3(2/-/)-one is a modulator of the adenosine A2A receptor.
  • Ebselen, 2-Phenyl-1 ,2- benzisoselenazol-3(2/-/)-one, or a pharmaceutically acceptable salts thereof is indicated for use in therapy as a modulator of the A2A receptor.
  • the present invention therefore provides the compound Ebselen, 2-Phenyl-1 ,2- benzisoselenazol-3(2/-/)-one, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition mediated by the adenosine A2A receptor.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound Ebselen, 2-Phenyl-1 ,2-benzisoselenazol-3(2/-/)-one, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the treatment or prevention of a disease or condition mediated by the adenosine A2A receptor.
  • the present invention provides a method of treating or preventing a disease or condition mediated by the adenosine A2A receptor, comprising administering to a patient in need thereof, a therapeutically effective amount of the compound Ebselen, 22-Phenyl-1 ,2-benzisoselenazol-3(2/-/)-one, or a pharmaceutically acceptable salt thereof.
  • Ebselen or a pharmaceutically salt thereof may be provided in the form of a pharmaceutical composition adapted for oral, intravenous, intradermal, subcutaneous, intramuscular, nasal, rectal, transdermal, transmucosal, intraperitoneal, or pulmonary administration, or by infusion, and may be used alone or in combination with another therapeutic agent
  • A2A receptors Upon activation, A2A receptors bind to Gs protein at the intracellular site of the receptor, which activates adenylyl cyclase, inducing the rise of intracellular cAMP.
  • Ebselen The affinity of Ebselen for the human adenosine A2A receptor in transfected HEK- 293 (human embryonic kidney) cells was determined in the radioligand binding assay described in Example 1 herein. Ebselen was found to bind to, and have the potential to modulate the activity of, the A2A receptor.
  • Ebselen Functional activity of Ebselen for the human adenosine A2A receptor in transfected HEK-293 cells was determined in the cAMP release assays described in Examples 2 and 3 herein. The results revealed Ebselen to be a partial agonist at the A2A receptor, and an antagonist of the A2A receptor, its action being concentration-dependent.
  • Ebselen is shown to be a modulator of the A2A receptor. As such, it is indicated in the treatment of or prevention of diseases or conditions mediated by the adenosine A2A receptor.
  • Ebselen includes both the compound Ebselen and its pharmaceutically acceptable salts.
  • the diseases and conditions contemplated in all aspects of the present invention comprise bleeding disorders.
  • applications of Ebselen contemplated in the present invention include prophylaxis of bleeding disorders.
  • Ebselen is contemplated in the treatment or prophylaxis of Haemophilia A, Haemophilia B, and von Willebrand’s disease.
  • Ebselen may be employed in combination with a recombinant Factor VIII, recombinant Factor IX and recombinant Factor XI.
  • Ebselen may be employed as an adjuvant treatment or in combination with a clotting factor such as one or more of Factor VIII, Factor IX and Factor XI. In some embodiments, Ebselen may be used as a replacement therapy in the treatment of bleeding and clotting disorders, either as regular treatments or for specific episodes such as during surgery.
  • a clotting factor such as one or more of Factor VIII, Factor IX and Factor XI.
  • Ebselen may be used as a replacement therapy in the treatment of bleeding and clotting disorders, either as regular treatments or for specific episodes such as during surgery.
  • Ebselen may also be used in diagnostic screens involved in bleeding disorders such as coagulation screens, coagulation factor assays, lupus acticoagulant testing, thrombophilia testing and platelet function testing.
  • the diseases and conditions contemplated in all aspects of the present invention comprise diseases of the reproductive system.
  • applications of Ebselen contemplated in the present invention include infertility, endometriosis and the prevention of premature birth (often caused by endometrial disorders).
  • A2A antagonists are known to relieve pain due to inflammation and peripheral neuropathy. Activation of A2AR by endogenous adenosine or exogenous agonists results in antinociception in case of inflammatory pain.
  • Ebselen as an A2AR modulator, it can be indicated for pain relief particularly in inflammatory conditions such as endometriosis.
  • bleeding indication is selected from the group consisting of Hemophilia A, Hemophilia B, Factor VIII deficiency, Factor XI deficiency, von Willebrand Disease, Glanzmann's Thrombasthenia, Bernard Soulier Syndrome, idiopathic thrombocytopenic purpura, and bleeding resulting from trauma;
  • a revascularization procedure for example performed on one or more of coronary arteries, renal arteries, leg arteries or carotid arteries and/or for example wherein the revascularization procedure is one of balloon angioplasty, insertion of a stent, insertion of a bypass graft, directional coronary atherectomy or percutaneous transluminal coronary angioplasty, or involves excimer laser angioplasty;
  • a pharmaceutical composition comprising the compound Ebselen, 2-Phenyl-1 ,2- benzisoselenazol-3(2H)-one, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the treatment or prevention of a disease or condition mediated by the adenosine A2A receptor.
  • the pharmaceutical composition may be adapted for example for oral, intravenous, intradermal, subcutaneous, intramuscular, nasal, rectal, transdermal, transmucosal, intraperitoneal, or pulmonary administration, or by infusion.
  • a method of treating or preventing a disease or condition mediated by the adenosine A2A receptor comprising administering to a patient in need thereof, a therapeutically effective amount of the compound Ebselen, 2-Phenyl-1 ,2- benzisoselenazol-3(2/-/)-one, or a pharmaceutically acceptable salt thereof, for example in the form of a pharmaceutical composition in accordance with the second aspect of the present invention.
  • Figure 1 illustrates the agonist response of Ebselen (HT6094) vs control at the A2A receptor, in the GPCR cAMP assay described in Example 2 herein.
  • Figure 2 illustrates the antagonist response of Ebselen (HT6094) vs control at the A2A receptor, in the GPCR cAMP assay described in Example 2 herein.
  • Figure 3 is a dose-response curve for Ebselen (HT6094) vs control in the A2A Human Adenosine GPCR Cell-Based Antagonist cAMP Assay described in Example 3 herein.
  • Receptor Source HEK-293 cells stably transfected with a plasmid encoding the human adenosine A2A receptor and were used to prepare membranes in modified Tris-HCI pH 7.4 (50 mM Tris-HCI, 10 mM MgCl2 and 2 Ul/ml ADA) buffer.
  • the fiber filters were rinsed several times with ice-cold 50 mM Tris-HCI using a 96-sample cell harvester (Unifilter, Packard).
  • Ebselen was screened at 10 pM.
  • the radioactive ligand in the experiment was [3H]CGS 21680 with Kd 27 nM.
  • Ebselen was purchased from Cayman Chemical (Item# 70530, www.caymanchem.com) with 99% purity. Ebselen was dissolved in DMSO.)
  • the standard reference compound is NECA, which was tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.
  • Ebselen (HT 6094) binds to A2AR 102.58% at 10 pM concentration compared to NECA. 10 pM of Ebselen inhibits 102.58% of agonist radioligand, suggesting Ebselen binds to A2ARs and has the potential to modulate the activity of the A2A receptor.
  • Table 1 The results are presented in Table 1 below, in which the given values represent binding as a percentage increase above the basal binding and are the average values from two assays.
  • Ebselen has any functional activity for the human adenosine A2A receptor in transfected HEK-293 (human embryonic kidney) cells.
  • cyclic adenosine monophosphate (cAMP) concentration is a widely used method to verify G-protein coupled receptor (GPCR) activation in the adenylyl cyclase pathway.
  • GPCR G-protein coupled receptor
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • Ebselen was purchased from Cayman Chemical (Item# 70530, www.caymanchem.com) with 99% purity. Ebselen was dissolved in DMSO for the assays.
  • DMSO containing Ebselen was incubated with HEK-293 Cells expressing A2ARs (1.25 x 10 A 5/ml) in modified HBSS, 5 mM HEPES, 0.1% BSA, 30 pM Rolipram) pH 7.4 buffer at 37°C for 10 minutes.
  • TR-FRET quantitation estimates cAMP accumulation (Gao et al. 2001 ; Poucher et al 1995).
  • Ebselen acts as a partial agonist in relatively higher concentrations when compared to the agonist activity of NECA. 10 pM of Ebselen also inhibited the NECA-induced cAMP response, suggesting its activity as an antagonist. In comparison to known antagonist ZM241385, Ebselen inhibited 90.74% of the activity of NECA-induced cAMP response. ( Figure 2). Ebselen binds and activates A2AR but did not elicit a complete response. These results are illustrated in Figure 2.
  • Ebselen is a partial agonist at A2ARs.
  • Ebselen binds to A2AR as determined by the binding studies, and it inhibited the action of the NECA (a potent agonist of A2ARs), suggesting it also acts as an antagonist.
  • NECA a potent agonist of A2ARs
  • Ebselen modulates A2ARs, and its activity depends on its concentration and presence/absence of other ligands.
  • TR- FRET immunoassay was used to measure cAMP produced upon modulation of adenylyl cyclase activity by adenosine A2A receptors expressed in HEK-293 cells.
  • Ebselen was purchased from Cayman Chemical (Item# 70530, www.caymanchem.com) with 99% purity. Ebselen was dissolved in DMSO for the assays.
  • Ebselen was screened at 100, 30, 10, 3, 1 , 0.3, 0.1 , 0.03, 0.01 and 0.003 pM concentrations.
  • control inhibitor ZM 241385 (0.014 pM IC50)
  • control activator NECA (0.0012 pM EC50) were used in the assay.
  • the assay was performed in 96 well plate format with 200pL volume. Ebselen were added at 100X stock dissolved in DMSO.
  • DMSO containing Ebselen was incubated with HEK-293 cells expressing A2A receptors (1.25 x 10 A 5/ml) in modified HBSS, 5 mM HEPES, 0.1% BSA, 30 pM Rolipram) pH 7.4 buffer at 37°C for 10 minutes.
  • TR-FRET quantitation estimates cAMP accumulation (**Gao et al. 2001 ; Poucher et al 1995).
  • a pharmaceutical composition comprising the compound Ebselen, 2- Phenyl-1 ,2-benzisoselenazol-3(2/-/)-one, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for use in the treatment or prevention of a disease or condition mediated by the adenosine A2A receptor.
  • a method of treating or preventing a disease or condition mediated by the adenosine A2A receptor comprising administering to a patient in need thereof, a therapeutically effective amount of the compound Ebselen, 2-Phenyl-1 ,2- benzisoselenazol-3(2H)-one, or a pharmaceutically acceptable salt thereof.
  • stenosis for example stenosis following a revascularisation procedure performed on, for example, coronary arteries, renal arteries, leg arteries and carotid arteries, for example involving any of balloon angioplasty, insertion of a stent, insertion of a bypass graft, directional coronary atherectomy, percutaneous transluminal coronary angioplasty and excimer laser angioplasty;
  • Guillain-Barre syndrome Guillain-Barre syndrome; pemphigus; cardiac inefficiency, for example for the improvement of contractile performance in a compromised myocardium or for the improvement of exercise tolerance; a brain disorder, for example for the improvement of the permeability of the bloodbrain barrier; symptoms of menopause; hypercalcaemia; hyperparathyroidism ;
  • Paget’s disease inflammation following implantation or plastic surgery; and a condition treated with a corticosteroid.

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Abstract

Ebselen, 2-phényl-1,2-benzisosélénazol-3(2H)-one, (I) est un modulateur du récepteur A2A de l'adénosine et est indiqué pour être utilisé dans le traitement ou la prévention d'une maladie ou d'un état à médiation par le récepteur A2A de l'adénosine.
PCT/GB2022/000014 2021-02-02 2022-02-01 Ebselen en tant que modulateur du récepteur de l'adénosine Ceased WO2022167778A1 (fr)

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GB2101401.4 2021-02-02
GBGB2101401.4A GB202101401D0 (en) 2021-02-02 2021-02-02 Ebselen as agonist of adnosine A2A receptors (A2AR)
GB2113514.0 2021-09-22
GB202113514 2021-09-22

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Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5021242A (en) * 1987-06-20 1991-06-04 A. Nattermann & Cie Gmbh Solid drug preparations containing micronized crystals of ebselen
US5484920A (en) 1992-04-08 1996-01-16 Kyowa Hakko Kogyo Co., Ltd. Therapeutic agent for Parkinson's disease
WO1996028163A1 (fr) 1995-03-13 1996-09-19 University Of Massachusetts Medical Center Adenosine a titre d'inotrope positif pour un coeur malade
WO1998057651A1 (fr) 1997-06-18 1998-12-23 Discovery Therapeutics, Inc. Compositions et procedes prevenant les restenoses consecutives a des interventions de revascularisation
US5877180A (en) 1994-07-11 1999-03-02 University Of Virginia Patent Foundation Method for treating inflammatory diseases with A2a adenosine receptor agonists
WO2003000694A1 (fr) 2001-06-22 2003-01-03 Almirall Prodesfarma S.A. Derives de 6-phenyldihydropyrrolopyrimidinedione
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