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WO2024163892A1 - Inhibition de la myéloperoxydase (mpo) en tant que cible de traitement pour une lésion cérébrale retardée (dci) dans une hémorragie sous-arachnoïdienne anévrismale (hsaa) - Google Patents

Inhibition de la myéloperoxydase (mpo) en tant que cible de traitement pour une lésion cérébrale retardée (dci) dans une hémorragie sous-arachnoïdienne anévrismale (hsaa) Download PDF

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Publication number
WO2024163892A1
WO2024163892A1 PCT/US2024/014250 US2024014250W WO2024163892A1 WO 2024163892 A1 WO2024163892 A1 WO 2024163892A1 US 2024014250 W US2024014250 W US 2024014250W WO 2024163892 A1 WO2024163892 A1 WO 2024163892A1
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alkoxy
mpo
alkyl
optionally
halogen
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WO2024163892A9 (fr
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Jose Javier PROVENCIO
Aminata P. COULIBALY
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UVA Licensing and Ventures Group
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University of Virginia Patent Foundation
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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
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • A61K9/08—Solutions
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • SAH Aneurysmal subarachnoid hemorrhage
  • DCI delayed cerebral injury
  • SAH aneurysmal subarachnoid hemorrhage
  • One aspect provides a method to prevent or treat cognitive dysfunction caused by delayed cerebral injury (DCI) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.
  • Another aspect provides a method to prevent or treat delayed cerebral injury (DCI) comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.
  • One aspect provides a method to prevent infiltration of neutrophils in the meninges comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.
  • a further aspect provides a method to reverse late memory deficits comprising administering to a subject in need thereof an effective amount of a small molecule inhibitor of MPO.
  • 1036.343WO1/PROVENJ-MPO (02901-02)
  • the administration is systemic administration.
  • the subject has had an aneurysmal subarachnoid hemorrhage (SAH).
  • the small molecule is one or more of N-Acetyl Lysyltyrosylcysteine Amide (KYC), an N-Acetyl Lysyltyrosylcysteine Amide (KYC) and/or a thioxanthine.
  • KYC N-Acetyl Lysyltyrosylcysteine Amide
  • KYC N-Acetyl Lysyltyrosylcysteine Amide
  • a thioxanthine is one or more of: In one aspect, the small molecule is a thioxanthine.
  • the thioxanthine is a compound of formula (I): 1036.343WO1/PROVENJ-MPO (02901-02) wherein at least one of X and Y represents S, and the other represents O or S; L represents (R 12 ) p -Q-(CR 13 R 14 ) r ; wherein (R 12 ) p and (CR 13 R 14 ) r each optionally contain one or two double or triple bonds; wherein Q is O, S(O) n , NR 6 , NR 6 C(O), C(O)NR 6 , or a bond; wherein R 12 is selected from Cl to 6 alkyl or Cl to 6 alkoxy, said Cl to 6 alkyl or said Cl to 6 alkoxy is optionally substituted with OH, halogen, CF 3 , CHF 2 , CFH 2 , CN, NR 4 R 5 , phenoxy or aryl; and wherein said phenoxy is optionally substituted with Cl to 6 al
  • X represents S and Y represents O.
  • L represents Cl to C7 alkylene. In one aspect, L represents Cl to C3 alkylene. In one aspect, L represents Cl alkylene. In one aspect, L represents C2 alkylene.
  • R 1 represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring may optionally be fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring alone, or said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF 2 , CH 2 F, CF 3, SO (n) R 9 , SO (n) NR 9 R 10 , OH, Cl to 7 alkyl, Cl to C7 alkoxy, CN, CONR 2 R 3 , NR 2 COR 3 and COR 3 ; said alkoxy being optionally further substituted by Cl to C
  • R 1 represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring, fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF 2 , CH 2 F, CF 3 , SO (n) R 9 , SO (n) NR 9 R 10 5 OH, Cl to C7 alkyl, Cl to C7 alkoxy, CN, CONR 2 R 3 , NR 2 COR 3 and COR 3 ; said alkoxy being optionally further substituted by Cl to C6 alkoxy, and said alkyl being optionally further substituted by
  • said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered 1036.343WO1/PROVENJ-MPO (02901-02) saturated, partially saturated or unsaturated ring, is substituted with halogen.
  • said halogen is selected from Cl and F.
  • the small molecule inhibitor is AZD5094. Brief Description of the Drawings Figures 1A-1D: A) Neutrophil percentage of inflammatory cells in the cerebral spinal fluid predicts cerebral vasospasm (CVs) by transcranial Doppler examination. The receiver operator curve suggests that 62% neutrophils is most predictive of CVs (2).
  • B) Neutrophil depletion using the anti-neutrophil antibody (anti-Ly6G) prevents the development of vasospasm in the middle cerebral artery when administered at day 3 after hemorrhage in a murine model of SAH (red box; vessel caliber not different than Sham) (ND neutrophil depletion).
  • FIG. 2A-2D A) Barnes maze test with Sham and SAH shows that the late memory deterioration seen in WT mice is abrogated in MPO KO mice. Instillation of MPO and H 2 O 2 (lower graph) returns the late deterioration event (red line) (1).
  • the middle panels are high magnification views of the white box from the upper panel.
  • the lower panels are normal brain (negative control), and two slices of EAE spinal cord (positive control) (3).
  • D) Mice deficient in myeloperoxidase (MPO KO) do not develop neutrophil infiltration of the meninges on day 3 after SAH (neutrophils in red. white bar 25um) (1).
  • FIGS 3A-3D A) Processed pictographs of meningeal blood vessels (red, stained with anti-CD31 Ab) and neutrophils (green, LysM-GFP) 6 days after SAH. Left panel shows SAH without treatment, middle panel shows SAH with intrathecal (into CSF) treatment with the MPO inhibitor AZD5904 at time of hemorrhage, right panel shows SAH with intraperitoneal (IP, a mouse surrogate for intravenous) treatment with the same MPO inhibitor 1036.343WO1/PROVENJ-MPO (02901-02) at the time of hemorrhage. B) Quantification of meningeal neutrophils shows IP treatment is most effective at decreasing meningeal neutrophil infiltration.
  • FIGS 5A-5B Meningeal cell line (Ben-Men 1 meningothelial cells) incubated with MPO (A) or neutrophils (B).
  • LPS is a positive control and H 2 O 2 is a substrate for MPO.
  • MPO and MPO with H 2 O 2 do not increase the secretion of IL-8, an inflammatory cytokine produced by meningothelial cells in response to stress.
  • Neutrophils cultured with meningothelial cells do increase IL-8 more than the positive control LPS. This suggests that a non-MPO effector function of neutrophils is responsible for IL-8 production.
  • DCI Delayed Cerebral Injury
  • SAH aneurysmal subarachnoid hemorrhage
  • CSF cerebrospinal fluid
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”
  • the terms “including,” “includes,” “having,” “has,” “with,” or variants thereof, are intended to be inclusive similar to the term “comprising.”
  • the term “about” can refer to a variation of ⁇ 5%, ⁇ 10%, ⁇ 20%, or ⁇ 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent.
  • the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. The term about can also modify the endpoints of a recited range as discuss above in this paragraph.
  • a recited range includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • contacting refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo.
  • An "effective amount” refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect.
  • an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art, especially in light of the detailed disclosure provided herein.
  • an “effective amount” is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host.
  • an “effective amount” generally means an amount that provides the desired effect.
  • treating include (i) preventing a disease, such as atherosclerosis, plaque buildup, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
  • a disease such as atherosclerosis, plaque buildup, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition.
  • the terms “treat”, “treatment”, and “treating” can extend to prophylaxis and can include prevent, 1036.343WO1/PROVENJ-MPO (02901-02) prevention, preventing, lowering, stopping or reversing the progression or severity
  • treatment can include medical, therapeutic, and/or prophylactic administration, as appropriate.
  • the terms “inhibit,” “inhibiting,” and “inhibition” refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, group of cells, protein or its expression.
  • the inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.
  • an “effective amount” or “therapeutically effective amount” means an amount sufficient to produce a selected effect, such as alleviating symptoms of a disease or disorder.
  • an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary.
  • the term “more effective” means that the selected effect is alleviated to a greater extent by one treatment relative to the second treatment to which it is being compared.
  • an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the peptide of the invention in the kit for effecting alleviation of the various diseases or disorders recited herein.
  • the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the identified compound invention or be shipped together with a container which contains the identified compound.
  • the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • sample from an unaffected subject refers to a sample obtained from a subject not known to have the disease or disorder being examined.
  • the sample may of course be a standard sample.
  • the term “otherwise identical” can also be used regarding regions or tissues in a subject or in an unaffected subject. 1036.343WO1/PROVENJ-MPO (02901-02)
  • standard refers to something used for comparison. For example, it can be a known standard agent or compound which is administered and used for comparing results when administering a test compound, or it can be a standard parameter or function which is measured to obtain a control value when measuring an effect of an agent or compound on a parameter or function.
  • Standard can also refer to an “internal standard”, such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured.
  • Internal standards are often a purified marker of interest which has been labeled, such as with a radioactive isotope, allowing it to be distinguished from an endogenous marker.
  • a “subject in need thereof” is a patient, animal, mammal, or human, who will benefit from the method of this invention.
  • the term “pharmaceutically acceptable carrier” means a chemical composition with which an appropriate compound or derivative can be combined and which, following the combination, can be used to administer the appropriate compound to a subject.
  • “Pharmaceutically acceptable” means physiologically tolerable, for either human or veterinary application.
  • “pharmaceutical compositions” include formulations for human and veterinary use. Methods involving conventional molecular biology techniques are described herein. Such techniques are generally known in the art and are described in detail in methodology treatises, such as Molecular Cloning: A Laboratory Manual, 2nd ed., vol.1-3, ed.
  • MPO Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17 (Location: Chr 17: 58.27 – 58.28 Mb ENSG00000005381, UniProt: P05164; mRNA: NM_000250; protein: NP_000241). MPO is most abundantly expressed in neutrophils (a subtype of white blood cells) and produces hypohalous acids to carry out their antimicrobial activity, including hypochlorous acid, the sodium salt of which is the chemical in bleach. It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation.
  • Neutrophil myeloperoxidase has a heme 1036.343WO1/PROVENJ-MPO (02901-02) pigment, which causes its green color in secretions rich in neutrophils, such as mucus and sputum. The green color contributed to its outdated name verdoperoxidase.
  • MPO metallocate-like protein
  • MPO a role in the collapse of the endothelial glycocalyx via binding with heparin sulfate and playing a role in shedding of syndecan1 in a neutrophile-dependent manner
  • MPO can transmigrate into various cell types (Kargapolova et al. Antioxidants.2021.10:562).
  • the 150-kDa MPO protein is a cationic heterotetramer consisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic heme group complex with calcium ions, arranged as a homodimer of heterodimers. Both are proteolytically generated from the precursor peptide encoded by the MPO gene.
  • the light chains are glycosylated and contain the modified iron protoporphyrin IX active site. Together, the light and heavy chains form two identical 73-kDa monomers connected by a cystine bridge at Cys153.
  • the protein forms a deep crevice which holds the heme group at the bottom, as well as a hydrophobic pocket at the entrance to the distal heme cavity which carries out its catalytic activity.
  • Variation in glycosylation and the identity of the heavy chain leads to variations in molecular weight within the 135-200 kDa range. In mice, three isoforms exist, differing only by the heavy chain.
  • Treatment/MPO Inhibitors Treatment and prevention of DCI has been a goal in the field of medicine since the 1980’s. Most therapies to date have been focused on the unlikely mechanism of spastic blood vessels leading to cerebral ischemia.
  • Nimodipine was first studied as a vasodilator (to reverse arterial vasospasm). Despite failing to affect vasospasm, the drug improved patient outcome. Two related drugs were successful at reversing vasospasm but did not improve patient outcomes. Nimodipine is now felt to be a mild neuroprotective agent. Other treatment modalities have focused on dilating spasmed blood vessels with fluid expansion of the vascular space, angioplasty, or intraarterial administration of vasodilators. None of these therapies have been shown to improve patient outcomes.
  • a CSF dialysis platform called Neuropheresis removed blood cells in the first few days after SAH. Pilot study data is published and shows promise. This technology has the disadvantage of being invasive and difficult to implement. It is not currently approved for use. 1036.343WO1/PROVENJ-MPO (02901-02)
  • MPO inhibitors used in animal studies and/or human clinical trials that work by blocking the catalytic site of MPO irreversibly.
  • the simplest is a 3 amino acid sequence called N-Acetyl Lysyltyrosylcysteine Amide (colloquially called KYC).
  • the second class are compounds that are N1-substituted-6-arylthiouracils.
  • thioxanthines e.g., 2-thioxanthines
  • MPO inhibitors that can be used in the methods provided herein: Azide, 4-aminobenzoic acid hydrazide (4-ABH), Additional examples of 2-thioxanthines include: 1036.343WO1/PROVENJ-MPO (02901-02) Additional thioxanthine compounds are provided below:
  • a compound of Formula (I), wherein L represents Cl to 7 alkylene In yet another aspect of the invention, there is provided a compound of Formula (I), wherein L represents Cl to 3 alkylene. In yet another aspect of the invention, there is provided a compound of Formula (I), wherein L represents Cl alkylene (methylene). In yet another aspect of the invention, there is provided a compound of Formula (I), wherein L represents C2 alkylene (ethylene).
  • R 1 represents a 5 or 6 membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S and said 5 or 6 membered heteroaromatic ring, fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S, and said ring system (said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring) being optionally substituted by one or more substituents independently selected from halogen, CHF 2 , alky 2 3 l, Cl to 7 alkoxy, CN, CONR R , NR 2 COR 3 and COR 3 ; said alkoxy being optionally further substituted by Cl to 6 alkoxy, and said alkyl being optionally further substituted by hydroxy or Cl to 6 alkoxy.
  • a compound of Formula (I) wherein said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring, is substituted with halogen.
  • a compound of Formula (I) wherein said halogen is selected from Cl and F. 1036.343WO1/PROVENJ-MPO (02901-02)
  • a compound of Formula (I) wherein said 5 or 6 membered heteroaromatic ring fused with a 5 or 6 membered saturated, partially saturated or unsaturated ring, is unsubstituted.
  • R 1 represents a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted by one or more substituents independently selected from halogen, CHF 2 , CH 2 F, CF 3 , SO (n) R 9 , SO (n) NR 9 R 10 , OH, Cl to 7 alkyl, Cl to 7 alkoxy, CN, CONR 2 R 3 , NR 2 COR 3 and COR 3 ; said alkoxy being optionally further substituted by Cl to 6 alkoxy, and said alkyl being optionally further substituted by hydroxy or Cl to 6 alkoxy.
  • R 1 represents a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, N and S, said aromatic ring being optionally substituted by one or more substituents independently selected from halogen, Cl to 6 alkyl and Cl to 6 alkoxy, said alkoxy being optionally further substituted by Cl to 6 alkoxy.
  • R represents a five- or six-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, said aromatic ring being optionally substituted by one or more substituents independently selected from halogen, CHF 2 , CH 2 F, CF 3 , SO (n) R 9 , SO (n) NR 9 R 10 , OH, Cl to 7 alkyl, Cl to 7 alkoxy, CN, CONR 2 R 3 , NR 2 COR 3 and COR 3 ; said alkoxy being optionally further substituted by Cl to 6 alkoxy.
  • a compound of Formula (I) wherein said five- or six-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, is substituted by one or more substituents independently selected from halogen and Cl to 7 alkyl.
  • a compound of Formula (I) wherein said heteroaromatic ring is selected from pyridyl and imidazolyl.
  • a compound of Formula (I) wherein said heteroaromatic ring is imidazolyl, substituted with halogen and Cl to 7 alkyl.
  • the present invention also relates to a compound, said compound being selected from: 3-(pyridin-2-ylmethyl)-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one; 3-(pyridin-3 -ylmethyl)-2-thioxo- 1 ,2,3 ,7-tetrahydro-6H-purin-6-one; 1036.343WO1/PROVENJ-MPO (02901-02) 3-(pyridin-4-ylmethyl)-2-thioxo-l,2,3,7-tetrahydro-6/f-purin-6-one; 3- ⁇ [3-ethoxy-4-(2-ethoxyethoxy)pyridin-2-yl]methyl ⁇ -2-thioxo-l,2,3,7-tetrahydro-6H " - purin- 6-one; 3-[(5-fluoro-lH " -indol-2-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro
  • the present invention also relates to a compound, said compound being selected from: 3-[2-(li7-Benzimidazol-2-yl)ethyl]-2-tliioxo-l ) 2,3,7-tetrahydro-6H " -purin-6-one; 3-(lH-Pyrazol-3-yhnethyl)-2-thioxo-l,2,3,7-tetrahydro-6H " -purin-6-one; 3-[(5-Methylpyrazm-2-yl)methyl)-2-thioxo-l,2,3,7-tetrahydro-6i7-purin-6-one; 3-[(3-Isopropylisoxazol-5-yl)methyl]-2-thioxo-l,2,3,7-tetrahydro-6H " -purin-6-one; 3-[(4-Methyl-l,2,5-oxadiazol-3-yl)methyl]-2-thioxo-l
  • the compounds of Formula (I) may exist in enantiomeric forms. Therefore, all enantiomers, diastereomers, racemates, tautomers and mixtures thereof are included within the scope of the invention.
  • the various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallization, or ⁇ PLC. Alternatively, the various optical isomers may be prepared directly using optically active starting materials.
  • the present invention includes compounds of Formula (I), in the form of salts. Suitable salts include those formed with organic or inorganic acids or organic or inorganic bases. Such salts will normally be pharmaceutically acceptable although salts of non- pharmaceutically acceptable acids or bases may be of utility in the preparation and purification of the compound in question.
  • acid addition salts include inter alia those 1036.343WO1/PROVENJ-MPO (02901-02) formed from hydrochloric acid or trifluoroacetic acid.
  • Base addition salts include those in which the cation is inter alia sodium or potassium.
  • the resultant compound of Formula (I), or another salt thereof, can where necessary be converted into a pharmaceutically acceptable salt thereof.
  • the compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and if necessary, further purified by using standard techniques. Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures. Intermediate compounds may also exist in tautomeric forms and may be used a purified tautomers or mixtures.
  • Cl to 6 alkylene or “Cl to 6 alkyl” referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, 1 -propyl, 1 -butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • Cl to 7 alkylene or “Cl to 7 alkyl” are to be interpreted analogously.
  • Examples of such groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, tert-butoxy and pentoxy.
  • the term "Cl to 7 alkoxy" is to be interpreted analogously.
  • the term "C2 to 6 alkanoyl” referred to herein denotes a straight or branched chain alkyl group having from 2 to 6 carbon atoms incorporating a carbonyl group. Examples of such groups include acetyl, propionyl and pivaloyl.
  • the term "halogen” referred to herein denotes fluoro, chloro, bromo and iodo.
  • a mono- or bicyclic heteroaromatic ring system containing one or more heteroatoms selected from N, O and S refers to a ring system containing one or more heteroatoms, however not more than 4 heteroatoms, selected from nitrogen, oxygen or sulphur.
  • Examples, but not limiting, of such ring systems are pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, triazole, oxadiazole, tetrazole, pyridine, pyrazine, pyrimidine and pyridazine, indole, isoindole, benzimidazole and quinoline, naphthyridine and imidazo[l ,2- a]pyridine.
  • the term "5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from C, N, O and S” refers to a ring containing 5 to 6 atoms of which 1 to 4 ring atoms are chosen from nitrogen, sulfur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked; and wherein, unless stated otherwise, a ring 1036.343WO1/PROVENJ-MPO (02901-02) sulphur atom is optionally oxidised to form the S-oxide(s).
  • rings examples, but not limiting, of such rings are tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyridine, morpholine, piperazine, thioazolidine, dihydrothiazolidine, pyrrolidinone and piperidinone and 1,1- dioxidotetrahydrothiophene.
  • Examples of a "5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from N, O or S" include, but is not limited to, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine and pyridazine.
  • Examples of a "5- or 6-membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S" include, but is not limited to, cyclopentane, cyclohexane, cyclohexene, cyclopentanone, tetrahydrofuran, pyrrolidine, piperidine, tetrahydropyridine, morpholine, piperazine, pyrrolidinone and piperidinone.
  • Examples of a "5- or 6-membered heteroaromatic ring containing one or more heteroatoms 5 selected from N, O or S" when fused with a "5 or 6 membered saturated, partially saturated or unsaturated ring containing one or more atoms selected from C, N, O or S" include, but is not limited to, indole, isoindole, benzimidazole and quinoline.
  • Examples of a "a mono- or bicyclic heteroaromatic ring system containing one or more I 0 heteroatoms selected from nitrogen, oxygen and sulfur; wherein said mono- or bicyclic heteroaromatic ring system is fused with one or two 5- or 6-membered saturated or partially saturated ring(s) containing one or more atoms selected from carbon, nitrogen, oxygen and sulfur” include, but is not limited to, indole, isoindole, benzimidazole and quinoline, naphthyridine, imidazo[l,2-a]pyridine.
  • L wherein L is defined to represents said (R 12 ) p bonds to N as seen in formula (I) and said (CR 13 R 14 ) r bonds to R 1 .
  • L is defined to represent "Cl to 7 alkylene; said alkylene 20 optionally incorporating a heteroatom selected from O, S(O) n and NR 6 ; said alkylene optionally incorporating one or two carbon-carbon double bonds
  • L is intended to embrace a saturated or unsaturated straight or branched chain arrangement of 1 to 7 carbon atoms having two free valencies and in which any two singly bonded carbon atoms are optionally separated by a saturated carbon atom bound to O, S or NR 6 .
  • Examples of a 5 to 7 membered saturated azacyclic ring optionally incorporating one 30 additional heteroatom selected from O, S and NR 11 include pyrrolidine, piperidine, 1036.343WO1/PROVENJ-MPO (02901-02) imindazolidine, pyrazolidine, piperazine, morpholine and thiomorpholine.
  • a further aspect of the present invention is the use of the compounds provided herein as a medicament to treat or prevent DCI after SAH.
  • a further aspect of the present invention is the use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme MPO is beneficial, including treating or preventing DCI after SAH.
  • a further aspect of the present invention provides the use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for the treatment or prevention of DCI after SAH. Further, there is also provided a method of treating, or reducing the risk of, DCI after SAH in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme MPO is beneficial, including for the treatment or prevention of DCI after SAH.
  • a pharmaceutically acceptable adjuvant, diluent or carrier for use in the treatment or prophylaxis of diseases or conditions in which inhibition of the enzyme MPO is beneficial, including for the treatment or prevention of DCI after SAH.
  • the compounds described herein can be administered in a standard manner such as orally, parenterally, transmucosally (e.g., sublingually or via buccal administration), topically, transdermally, rectally, via inhalation (e.g., nasal or deep lung inhalation).
  • Parenteral administration includes, but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal or via a high-pressure technique.
  • the composition can be in the form of tablets or lozenges formulated in conventional manner.
  • tablets and capsules for oral administration can contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (e.g., magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g., potato 1036.343WO1/PROVENJ-MPO (02901-02) starch or sodium starch glycollate), or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • fillers e.g., lacto
  • Tablets may be coated according to methods well known in the art.
  • Such preparations can also be formulated as suppositories for rectal administration, e.g., containing conventional suppository bases, such as cocoa butter or other glycerides.
  • Compositions for inhalation typically can be provided in the form of a solution, suspension, or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant, such as dichlorodifluoromethane or trichlorofluoromethane.
  • Typical topical and transdermal formulations comprise conventional aqueous or non-aqueous vehicles, such as eye drops, creams, ointments, lotions, and pastes, or are in the form of a medicated plaster, patch, or membrane.
  • compositions described herein can be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing, and/or dispersing agents.
  • the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
  • a composition in accordance with the present invention also can be formulated as a depot preparation.
  • Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the present invention can be formulated with suitable polymeric or hydrophobic materials (e.g., an emulsion in an acceptable oil), ion exchange resins, or as sparingly soluble derivatives (e.g., a sparingly soluble salt).
  • suitable polymeric or hydrophobic materials e.g., an emulsion in an acceptable oil
  • ion exchange resins e.g., ion exchange resins
  • sparingly soluble derivatives e.g., a sparingly soluble salt
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be used to form tablets.
  • Solid compositions of a similar type are also employed as fillers in soft and hard- filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the compounds/composition described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example.
  • formulations containing these compounds can be presented as 1036.343WO1/PROVENJ-MPO (02901-02) a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can contain conventional additives, such as suspending agents, such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin, glucose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminum stearate gel, emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol; and preservatives, such as methyl or propyl p- hydroxybenzoate and sorbic acid.
  • suspending agents such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,
  • aqueous suspensions and/or elixirs are desired for oral administration, the compounds described herein can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the compounds described herein can also be administered in a controlled release formulation such as a slow release or a fast release formulation.
  • controlled release formulations of the combinations described herein may be prepared using methods well known to those skilled in the art. The method of administration will be determined, by the attendant physician or other person skilled in the art after an evaluation of the patient's condition and requirements.
  • the effective dose of a MPO inhibitor or a pharmaceutically acceptable salt thereof and a compound or a pharmaceutically acceptable salt thereof, which is used in the treatment and/or prevention of DCI after SAH in the combinations according to the present invention may vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder as well as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, and the like. Determining a dose is within the skill of the ordinary artisan. 1036.343WO1/PROVENJ-MPO (02901-02) The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain therapeutic effects.
  • the effective dose of MPO inhibitors or a pharmaceutically acceptable salt thereof generally requires administering the compound in a range of from, and including, 1 to 1000 mg.
  • said range is from, and including, 2 to 800 mg or from, and including, 2 to 400 mg.
  • the amount of MPO inhibitor or a pharmaceutically acceptable salt thereof is selected from about: 5, 10, 50, 100, 150, 200, 250, 300, 350, 400, 500, 550, 600, 700 and 800 mg.
  • the effective dose compound or a pharmaceutically acceptable salt thereof, which is used in the treatment and/or prevention of DCI after SAH generally requires administering the compound in a range of from, and including, 1 to 1000 mg.
  • said range is from, and including, 2 to 800 mg or from, and including, 2 to 400 mg.
  • the amount of compound or a pharmaceutically acceptable salt thereof, which is used in the treatment and/or prevention of DCI after SAH is selected from about: 5, 10, 50, 100, 150, 200, 250, 300, 350, 400, 500, 550, 600, 700 and 800 mg.
  • therapeutically effective amount refers to a sufficient amount of the compound to treat DCI after SAH at a reasonable risk/benefit ratio applicable to any medical treatment.
  • treating refers to reversing, alleviating, delaying or inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of “treating” as defined herein.
  • disorder unless stated otherwise, has the same meaning as the terms “condition” and “disease” and are used interchangeably throughout the description and claims.
  • agent or “drug” means the compounds of the present invention. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain therapeutic effects.
  • SAH Aneurysmal subarachnoid hemorrhage
  • SAH Unlike ischemic stroke that has an average age in the 7 th decade of life and less frequently affects young people, SAH has a broad age distribution from the teens to octogenarians with a median age in the early 50’s. SAH tends to affect younger patients, including some in their 20’s and 30’s who are still in the prime of their productive lives. In addition, the disability among survivors of SAH includes both physical and cognitive disability (7-9). Patients who develop delayed cerebral injury (DCI) experience cognitive deficits (more than strength deficits) that leave patients homebound, unable to work and needing supervision. This has ramifications for patients, their family members in the workforce, on community resource needs, and national health care costs.
  • DCI delayed cerebral injury
  • DCI delayed cerebral injury
  • DCI Delayed cerebral injury
  • SAH Stayed cerebral injury
  • the syndrome includes alteration in mental status (with occasional focal neurological signs) which is often associated with fever, hyponatremia, and evidence of cerebral vasospasm (12).
  • DCI was previously assumed to be due to ischemia (stroke) from arterial vasoconstriction (vasospasm), but treatment trials addressing arterial vasospasm in DCI have not improved outcomes suggesting that: 1) non-ischemic mechanisms are involved, and 2) vascular disease leading to ischemia is a small determinant of outcome.
  • the treatment strategies for DCI have focused on the associated cerebral vasospasm.
  • the armamentarium of treatments includes one preventative medication (nimodipine) and reactive strategies to improve cerebral blood flow by volume expansion/hypertension or by direct intraarterial vasodilation of decreased caliber arteries (12).
  • imodipine preventative medication
  • DCI leads to long-term disability in a large proportion of survivors.
  • the time delay between the hemorrhage and the onset of DCI is a potential window of opportunity for treatment that is not present in other types of cerebrovascular injury (15).
  • DCI DCI, often called Delayed Cerebral Ischemia
  • ischemia from arterial vasospasm (constriction of blood vessels) despite clinical trials of vasodilation failing to improve outcome (21-23).
  • Controversy exists regarding the etiology of brain injury in DCI.
  • Colloquially called “cerebral vasospasm” due to its association with arterial spasm on angiography, this association with vascular spasm has overly-simplistically led to the conclusion that ischemia is the major driver of pathology.
  • Three human trials of vasodilators have called this into question.
  • nimodipine a calcium channel blocker
  • nicardipine another calcium channel blocker, and clazosentan, an endothelin-1 antagonist, ameliorate vascular spasm but do not improve patient outcome (22,23,25,26).
  • the finding that: 1) patient outcome can be improved without improving 1036.343WO1/PROVENJ-MPO (02901-02) vasospasm and 2) that vasospasm can be improved without patient benefit makes ischemia as the driver of disability unlikely.
  • Positron emission tomography (PET) blood flow scanning data support the findings of the clinical trials.
  • EBI early brain injury
  • ischemic stroke is an outcome (34).
  • cerebral vasospasm, EBI and micro-thromboses can lead to histological evidence of brain damage (35). The totality of the evidence does not support that these mechanisms are the major driver of long-term cognitive deficits in most patients who experience DCI after SAH.
  • Inflammation has been identified as the mechanism most likely determinant of outcome in DCI (16,17). It is believed that inflammation plays a role in initiating DCI after SAH. Peripheral blood leukocyte counts in the first 2 days of SAH predict who will develop “cerebral vasospasm” (36,37).
  • Cytokine analysis of the blood of 1036.343WO1/PROVENJ-MPO (02901-02) patients with SAH also suggests inflammation is associated with DCI, and poor outcome (41,42).
  • Biomarker analysis shows that TNF ⁇ levels predict poor outcome (43).
  • DCI The search for cellular actors in the development of DCI has implicated several cells that appear to play a role. There is evidence that endothelial cell interactions with circulating leukocytes drive the onset of DCI (40). In addition, microglia, resident brain inflammatory cells, have been implicated in promoting inflammation after SAH (44). In addition to cells local to the brain, systemic inflammatory cells have been associated with DCI. Interestingly, the late onset of DCI would suggest a role for the adaptive immune system (T cells and B cells), but research suggests that cells of the innate immune system play a larger role. Monocytes and macrophages increase over the first few days in animal models of SAH and, when sequestered away from the brain, appear to confer benefit to the development of inflammation after SAH (45).
  • neutrophil a protein produced by neutrophils, Myeloperoxidase (MPO).
  • MPO Myeloperoxidase
  • Neutrophils are part of the innate immune system. In infection, they are an early actor in inflammation, and make up more than 90% of cells found in pus. However, neutrophils appear to act differently in sterile injuries (where there is no infection but inflammation) than in bacterial infections. In sterile diseases outside the nervous system (in arthritis and other autoimmune disorders,) neutrophils play a delayed role (46-48). In the setting of SAH, patients who go on to develop DCI show an increase in neutrophils in the CSF three (3) days after hemorrhage ( Figure 1A) (2).
  • MPO is an intermediary in this neutrophil-mediated brain damage after SAH ( Figure 4).
  • SAH neutrophil depletion/inactivation and MPO inhibition prevent the development of DCI and its downstream cognitive consequences.
  • the conclusion that neutrophils and MPO play a role in the development of DCI is based on both human and animal model data.
  • Neutrophils as a percentage of leukocytes, found in the cerebral spinal fluid (CSF) of patients with SAH three days after the hemorrhage is a predictor of arterial vasospasm (a biomarker for DCI).
  • CSF cerebral spinal fluid
  • KO MPO knockout
  • RNA sequencing data and better flow cytometric techniques the meninges have been found to have a rich landscape of immune cells, and more recently, functional consequences for the brain (reviewed in 53).
  • interferon gamma (INF ⁇ ) produced from T cells in the meninges affects sociability behavior in mice (54).
  • Meningeal lymphatic channels play a role in immune surveillance and coordinate with the brain glymphatic system to monitor brain solutes for infection, inflammation, and abnormal cells (55,56).
  • the role of meningeal neutrophils is an active area of investigation. Neutrophils make up the largest proportion of inflammatory cells in the meninges (27%) (57). In SAH, few neutrophils enter the brain.
  • neutrophils accumulate in the perivascular spaces and in the meninges ( Figure 2B).
  • the time course of neutrophil infiltration in mice correlates with the critical period of neutrophil depletion (1,5).
  • Prevention of neutrophil infiltration into the 1036.343WO1/PROVENJ-MPO (02901-02) meninges by blocking RoR ⁇ T, a transcription factor for IL-17, a potent homing agent for neutrophils into tissues decreases inflammation in the brain and neutrophil infiltration of the meninges (Figure 2C) (4).
  • MPO KO mice do not develop meningeal infiltration by neutrophils suggesting that MPO also plays a role in homing of neutrophils into the meninges (Figure 2D) (1).
  • mice receiving the inhibitor had decreased latency to goal box on a spatial memory task (Barne’s maze) over the 10 days of the experiment (top panel). Cumulative heat maps of the entire experimental group on days 3, 5 ,7 and 9 show the mice who receive the inhibitor make contralateral-hole-search errors less frequently.
  • a series of cell culture experiments where MPO or activated neutrophils were co- cultured with cells of the meninges showed that neutrophils, but not MPO alone, lead to the release of signaling molecules (particularly, the cytokine IL-8) that are implicated in the development of DCI. This shows that MPO is not a downstream actor in development of cognitive deficits after SAH (Figure 5).
  • CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care. Apr 2010;12(2):244-51. doi:10.1007/s12028-009-9308-7 3.
  • Wijdicks EF Vermeulen M, ten Haaf JA, Hijdra A, Bakker WH, van Gijn J. Volume depletion and natriuresis in patients with a ruptured intracranial aneurysm. Ann Neurol. Aug 1985;18(2):211-6. doi:10.1002/ana.410180208. 35. Prunell GF, Svendgaard NA, Alkass K, Mathiesen T. Delayed cell death related to acute cerebral blood flow changes following subarachnoid hemorrhage in the rat brain. J Neurosurg. Jun 2005;102(6):1046-54. doi:10.3171/jns.2005.102.6.1046 36.
  • Provencio, J.J., et al., CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care, 2010.12(2): p.244-51.
  • Provencio, J.J., et al., Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors. Brain Behav Immun, 2016.54: p.233-242.

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Abstract

L'invention concerne un procédé pour prévenir ou traiter un dysfonctionnement cognitif provoqué par une lésion cérébrale retardée (DCI) après une hémorragie sous-arachnoïdienne anévrismale (HSAa) comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un inhibiteur à petites molécules de MPO.
PCT/US2024/014250 2023-02-02 2024-02-02 Inhibition de la myéloperoxydase (mpo) en tant que cible de traitement pour une lésion cérébrale retardée (dci) dans une hémorragie sous-arachnoïdienne anévrismale (hsaa) Ceased WO2024163892A1 (fr)

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WANG YUN-CHANG, LU YU-BAO, HUANG XIAO-LAN, LAO YONG-FENG, ZHANG LU, YANG JUN, SHI MEI, MA HAI-LONG, PAN YA-WEN, ZHANG YI-NIAN: "Myeloperoxidase: a new target for the treatment of stroke?", NEURAL REGENERATION RESEARCH, MEDKNOW PUBLICATIONS AND MEDIA PVT. LTD., CN, vol. 17, no. 8, 1 January 2022 (2022-01-01), CN , pages 1711, XP093200036, ISSN: 1673-5374, DOI: 10.4103/1673-5374.332130 *
YU GUOLIANG, LIANG YE, HUANG ZIMING, JONES DERON W., PRITCHARD KIRKWOOD A., ZHANG HAO: "Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke", JOURNAL OF NEUROINFLAMMATION, BIOMED CENTRAL LTD., LONDON, GB, vol. 13, no. 1, 1 December 2016 (2016-12-01), GB , XP093200045, ISSN: 1742-2094, DOI: 10.1186/s12974-016-0583-x *
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