WO1999008680A1 - Procede d'utilisation d'inhibiteurs selectifs de parp pour prevenir ou traiter la neurotoxicite - Google Patents

Procede d'utilisation d'inhibiteurs selectifs de parp pour prevenir ou traiter la neurotoxicite Download PDF

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WO1999008680A1
WO1999008680A1 PCT/US1998/016959 US9816959W WO9908680A1 WO 1999008680 A1 WO1999008680 A1 WO 1999008680A1 US 9816959 W US9816959 W US 9816959W WO 9908680 A1 WO9908680 A1 WO 9908680A1
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parp
selective
adp
selective inhibitor
inhibitor
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PCT/US1998/016959
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English (en)
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Mikael J. Eliasson
Kenji Sampei
Allen S. Mandir
Patricia D. Hurn
Richard J. Traystman
Jun Bao
Andrew Pieper
Ted M. Dawson
Solomon H. Snyder
Valina L. Dawson
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The Johns Hopkins University
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Priority to AU87846/98A priority Critical patent/AU8784698A/en
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Priority to US09/502,046 priority patent/US6358975B1/en

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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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • the invention relates to the prevention and/or treatment of neural tissue damage resulting from ischemia and reperfusion injury. More particularly, the invention concerns the prevention or treatment of vascular stroke, other neurodegenerative diseases and occlusion of coronary arteries, by administering selective inhibitors of the nucleic enzyme poly(adenosine 5'- diphospho-ribose) polymerase ["poly(ADP-ribose) polymerase” or "PARP”, which is also sometimes called “PARS” for poly(ADP-ribose) synthetase].
  • PARP poly(ADP-ribose) polymerase
  • PARP Poly(ADP-ribose) polymerase
  • PARP plays a physiological role in the repair of strand breaks in DNA. Once activated by damaged DNA fragments, PARP catalyzes the attachment of up to 100 ADP- ribose units to a variety of nuclear proteins, including histones and PARP itself. While the exact range of functions of PARP has not been established, this enzyme is thought to play a role in enhancing DNA repair. During major cellular stresses, however, the extensive activation of PARP can rapidly lead to cell death through depletion of energy stores.
  • NAD the source of ADP- ribose
  • Neural damage following stroke and other neurodegenerative processes is thought to result from a massive release of the excitatory neurotransmitter glutamate, which acts upon the N-methyl-D-aspartate (NMDA) receptors and other subtype receptors.
  • NMDA N-methyl-D-aspartate
  • Evidence includes findings in many animal species, as well as in cerebral cortical cultures treated with glutamate or NMDA, that glutamate receptor antagonists block neural damage following vascular stroke. Dawson et al., "Protection of the Brain from Ischemia", Cerebrovascular
  • NMDA receptors activate neuronal nitric oxide synthase (nNOS), which causes the formation of nitric oxide (NO), which more directly mediates neurotoxicity. Protection against NMDA neurotoxicity has occurred following treatment with NOS inhibitors.
  • Figure 5 provides a simple model of the following sequence of the multitude of cellular events that presumably takes place in the PARP activation associated with ischemia:
  • Ischemia following blood vessel occlusion reduces the resting membrane potential of glia and neurons in the tissue.
  • glutamate triggers a release of NO, which combines with superoxide to form peroxynitrite.
  • ATP is depleted in an effort to re-synthesize NAD, leading to cell death by energy depletion.
  • NO is a free radical that reacts chemically with multiple cellular targets to elicit a range of activities from cellular signalling to cell death. Most of the toxic effects of NO appear to be a result of the reaction of NO with superoxide to form the extremely toxic peroxynitrite. See Beckman et al., "Pathological Implications of Nitric Oxide, Superoxide and Peroxynitrite Formation", Biochem. Soc. Trans., 21330-34 (1993). Either NO or peroxynitrite can cause DNA damage, which activates PARP.
  • PARP activation plays a key role in both NMDA- and NO- induced neurotoxicity, as shown by the use of PARP inhibitors to prevent such toxicity in cortical cultures in proportion to their potencies as inhibitors of this enzyme (Zhang et al., "Nitric Oxide Activation of Poly(ADP-ribose) Synthetase in Neurotoxicity", Science, 263:786-89 (1994)) and in hippocampal slices (Wallis et al., "Neuroprotection against Nitric Oxide Injury with Inhibitors of ADP- ribosylation, Neuroreport, 5:313, 245-48 (1993)). Zhang et al., U.S. Patent No.
  • PARP activation has been shown to provide an index of damage following neurotoxic insults, not only by glutamate (via NMDA receptor stimulation) and reactive oxygen intermediates, but also by amyloid ⁇ -protein, n-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP + ), which participate in such pathological conditions as stroke, Alzheimer's disease and Parkinson's disease.
  • MPTP amyloid ⁇ -protein
  • MPTP n-methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine
  • MPP + active metabolite N-methyl-4-phenylpyridine
  • non-selective PARP inhibitors The occurrence of side effects observed with non-selective PARP inhibitors are discussed in Milam et al., "Inhibitors of Poly(Adenosine Diphosphate-Ribose) Synthesis: Effect on Other Metabolic Processes," Science, 223:589-91 (1984). Specifically, the non-selective PARP inhibitors 3- aminobenzamide and benzamide not only inhibited the action of PARP but also were shown to affect cell viability, glucose metabolism, and DNA synthesis. Thus, it was concluded, the usefulness of these particular PARP inhibitors may be severely restricted by the difficulty of finding a dose small enough to inhibit the enzyme without producing additional metabolic effects.
  • Banasik et al. in "Specific Inhibitors of Poly(ADP-Ribose) Synthetase and Mono(ADP- ribosyl)transferase", J. of Biol. Chem., 267:1569-75 (1992), identified four compounds that were particularly good inhibitors of PARP, i.e., free of side reactions and applicable to in vivo studies. They were 4-amino-1 ,8- naphthalimide, 6(5H)- and 2-nitro-6(5H)- ⁇ henanthridinones and 1 ,5- dihydroxyisoquinoline.
  • the method of preventing neural tissue damage resulting from ischemia and reperfusion injury or neurodegenerative diseases in a mammal in accordance with the invention comprises administering to the mammal a therapeutically effective amount of a selective inhibitor of poly(ADP-ribose) polymerase (PARP).
  • PARP poly(ADP-ribose) polymerase
  • Figure 1 shows a plot of percentage of cell death vs. molar concentration comparing the activity of the non-selective PARP inhibitor benzamide (BZD) with the specific PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)-butox]-1 (2H)- isoquinolinone (DPQ).
  • Figure 2A shows the percentage of cell death when wild-type, PARP+/- and PARP-/- cells are subjected to treatment with the neurotoxic agents NMDA, oxygen-glucose deprivation (OGD), sodium nitroprusside (SNP), and 3- morpholino-sydnonimine hydrochloride (SIN-1 ).
  • OGD oxygen-glucose deprivation
  • SNP sodium nitroprusside
  • SIN-1 3- morpholino-sydnonimine hydrochloride
  • Figure 2B compares the percentage of cell death when wild-type, PARP+/- and PARP-/- cells, which have been subjected to treatment with NMDA, are further treated with MK801 , nitroarginine (NArg), a combination of NArg and L-arginine (LArg), benzamide (BZD) or 3,4-dihydro-5-[4-(1-piperidinyl)-butox]- 1(2H)-isoquinolinone (DPQ).
  • NArg nitroarginine
  • LArg L-arginine
  • BZD benzamide
  • DPQ 3,4-dihydro-5-[4-(1-piperidinyl)-butox]- 1(2H)-isoquinolinone
  • Figure 2C compares the percentage of cell death when wild-type, PARP+/- and PARP-/- cells, which have been subjected to oxygen-glucose deprivation (OGD), and are then treated with MK801, nitroarginine (NArg), a combination of NArg and L-arginine (LArg), benzamide (BZD) or 3,4-dihydro-5-[4-(1-piperidinyl)-butox]-1(2H)-isoquinolinone (DPQ).
  • OGD oxygen-glucose deprivation
  • Figure 3A shows the infarct volume of forebrains after transient focal ischemia in wild-type, PARP+/- and PARP-/- mice.
  • Figure 3B shows the infarct area in coronal slices of forebrains after transient focal ischemia in wild-type, PARP+/- and PARP-/- mice.
  • Figure 4 shows the regional cerebral blood flow before, during, and after two hours of middle cerebral artery occlusion in wild-type, PARP+/- and PARP-/- mice.
  • Figure 5 shows a simple model of PARP activation in ischemia. DETAILED DESCRIPTION OF THE INVENTION
  • PARP activation is primarily involved in neural tissue damage, including that following focal ischemia and reperfusion injury.
  • Selective therapies designed to inhibit PARP directly and specifically can provide significant benefits in the treatment of, e.g., cerebrovascular disease or neurodegenerative diseases, as compared with therapies designed to block glutamate production, NMDA activity, NO production or NOS activity.
  • inhibition of PARP activity spares the cell from energy loss, preventing irreversible depolarization of the neurons and, thus, provides neuroprotection.
  • PARP activation may play a common role in still other excitotoxic mechanisms, perhaps as yet undiscovered, in addition to the production of free radicals and NO.
  • neural tissue damage resulting from ischemia and reperfusion injury and neurodegenerative diseases includes neurotoxicity, such as seen in vascular stroke and a number of neurodegenerative diseases, for example, Alzheimer's disease, Parkinson's disease and Huntingtin's disease.
  • selective PARP inhibitor refers to a PARP inhibitor that has its major inhibitory effect specifically at the PARP receptor site, as opposed to blocking PARP activity by interfering with other biological pathways.
  • examples of such other biological pathways include NMDA- neurotoxicity or other NO-related activity that occurs biologically upstream from direct PARP activation, and also inhibitors of mono(ADP-ribosyl)transferases. It has been found that, when the PARP receptor site can be blocked selectively, a concentration sufficient to produce the desired degree of PARP inhibition can be used without incurring the risk of deleterious side effects.
  • Such an inhibitor would be capable of completely eliminating enzyme activity without undesirable side effects and thereby produce much greater protection against neurotoxicity than is possible with methods previously used.
  • selective PARP inhibition provides impressive protection against vascular damage in stroke, reducing the infarct volume by as much as
  • selective PARP inhibitors of the invention include certain benzamide derivatives, phenanthridones, isoquinolines, dihydroisoquinolines, dihydroxyisoquinolines, isoquinolinones, quinazolines, quinazolinones, naphthalimides, hydroxybenzamides, or the pharmacologically acceptable base or acid addition salts thereof, or mixtures thereof.
  • the selective inhibitor of the invention is selected from the group consisting of isoquinolines, dihydroisoquinolines, dihydroxyisoquinolines, isoquinazolinones, naphthalamides, and the pharmacologically acceptable base or acid addition salts thereof.
  • the selective inhibitor is an isoquinolinone.
  • useful inhibitors include: benzoyleneurea, 3-acetamidobenzamide,
  • the selective inhibitor is 3,4-dihydro-5-[4-(1-piperidinyl)-butox]-
  • DPQ (2H)-isoquinolinone
  • Examples of general groups of non-selective PARP inhibitors include unsaturated long-chain fatty acids.
  • Other families of PARP inhibitors for example, the benzamides and the quinazolines, may have some specific compounds that are highly selective and some specific compounds that are not particularly selective. Specifically, benzamide and some of its derivatives such as benzoic acid, 3-aminobenzamide and 4-aminobenzamide are recognized as being non-selective, while 3-acetamidobenzamide, 3-chlorobenzamide, 3- hydroxybenzamide, 3-methylb ⁇ nzamide, 3-methoxybenzamide, may be selective to some degree. Further, while quinazoline itself does not appear to be PARP- selective, the specific derivative 2-methyl-4(3H)-quinozoline does seem to inhibit PARP selectivity over the similar enzyme receptor site for mono(ADP-ribose) transferase.
  • a convenient method to determine quickly and easily whether a PARP inhibitor compound is selective or non-selective with respect to the PARP receptor site, as opposed to upstream sites for NMDA- or NO-related inhibition is to treat a cortical cell culture (1 ) first with the PARP inhibitor being tested to exert a neuroprotective effect, (2) then with an amount of NMDA usually sufficient to induce a neurotoxic condition, (3) then with a selective NOS inhibitor, such as nitroarginine, in an amount usually sufficient to counteract NMDA-induced neurotoxicity, and (4) finally, with a substance that reverses the neuroprotective of the NOS inhibitor such as arginine.
  • the neuroprotective effect was due to NO-inhibition, upstream of the true PARP receptor site, neurotoxic conditions will return upon the addition of the antagonist to NO- inhibition.
  • the neuroprotective effect was selective at the point of PARP activation, downstream from NO-production, the neuroprotective effect should persist, even after the addition of the NO-inhibitor antagonist.
  • a convenient method to determine quickly and easily whether a PARP inhibitor compound is selective or non-selective with respect to the PARP receptor site, as opposed to that of mono(ADP-ribosyl)transferase, is to compare IC 50 values for the inhibitor being tested for PARP and for another arginine- specific mono(ADP-ribosyl)transferase, for example, from hen heterophils by the procedure of Tanigawa et al., "ADP-ribosyltransferase from Hen Liver Nuclei:
  • Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids, such as hydrochloric acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the corresponding hydrochloride, sulfamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, respectively of those derived from the neutral compound.
  • mineral acids such as hydrochloric acid and sulfuric acid
  • organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like
  • suitable inorganic bases for the formation of salts of compounds of the invention include the hydroxides, carbonates, and bicarbonates of ammonia; sodium; lithium; potassium; calcium; magnesium; aluminum; zinc; and the like. Salts may also be formed with suitable organic bases.
  • Organic bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include those that are non-toxic and strong enough to form such salts.
  • the class of such organic bases may include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and triethylamine; mono-, di- or trihydroxyaikylamines, such as mono-, di-, and triethanolamine; amino acids, such as arginine and lysine; guanidine; N-methylglucosamine; N- methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; (trihydr ⁇ xymethyl)aminoethane; and the like. See, for example, "Pharmaceutical Salts," J. Pharm. Sci., 66:1 , 1-19 (1977).
  • the acid addition salts of the basic compounds may be prepared either by dissolving the free base of a selective PARP inhibitor in an aqueous or an aqueous alcohol solution or other suitable solvent containing the appropriate acid or base, and isolating the salt by evaporating the solution.
  • the free base of the selective PARP inhibitor may be reacted with an acid, as well as reacting the PARP inhibitor having an acid group thereon with a base, such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution.
  • selective PARP inhibitors typically have an ICso for inhibiting poly(ADP-ribose) polymerase in vitro of 33 ⁇ M or lower, preferably 22 ⁇ M or lower and, even more preferably, 40 nM or lower.
  • non-selective PARP inhibitors such as benzamide and its derivatives are relatively weak PARP inhibitors with poor bioavailability.
  • benzamide only provides about a 50% protection against NMDA neurotoxicity. See, for example, Zhang et al. "Nitric Oxide
  • a selective PARP inhibitor in the method of the invention may be oral, parenteral (intravenous, subcutaneous, intramuscular, intraspinal, intraperitoneal, and the like), rectal, intraventricular, or any other convenient dosage form.
  • the PARP inhibitor When administered parenterally, the PARP inhibitor will normally be formulated in a unit dosage, injectable form (solution, suspension or emulsion) with a pharmaceutically acceptable vehicle.
  • a pharmaceutically acceptable vehicle are preferably non-toxic and non-therapeutic.
  • Examples of such vehicles include water; aqueous solutions, such as saline, Ringer's solution, dextrose solution, and Hanks' solution; and nonaqueous vehicles, such as fixed oils (e.g., com, cottonseed, peanut, and sesame oil), ethyl oleate, and isopropyl myristate.
  • aqueous solutions such as saline, Ringer's solution, dextrose solution, and Hanks' solution
  • nonaqueous vehicles such as fixed oils (e.g., com, cottonseed, peanut, and sesame oil), ethyl oleate, and isopropyl myristate.
  • fixed oils e.g., com, cottonseed, peanut, and sesame oil
  • ethyl oleate ethyl oleate
  • isopropyl myristate e.g., com, cottonseed, peanut, and sesame oil
  • the PARP inhibitors When administered orally (or rectally), the PARP inhibitors will usually be formulated into a unit dosage form such as a tablet, capsule, suppository or cachet.
  • Such formulations typically include a solid, semisolid, or liquid carrier or diluent.
  • Exemplary diluents and vehicles include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and the like.
  • the selective PARP inhibitor of the invention is preferably administered as a capsule or tablet containing a single or divided dose of the inhibitor.
  • the selective PARP inhibitor is administered as a sterile solution, suspension, or emulsion, in a single or divided dose.
  • the selective PARP inhibitors are used in amounts that are therapeutically effective. While the effective amount of the PARP inhibitor will depend on the particular inhibitor being used, amounts of the PARP inhibitor varying from about 1% to about 65% have been easily incorporated into liquid or solid delivery systems.
  • Doses of the compounds preferably include pharmaceutical dosage units comprising an efficacious quantity of active compound.
  • an efficacious quantity is meant a quantity sufficient to inhibit PAR and derive the beneficial effects therefrom through administration of one or more of the pharmaceutical dosage units.
  • the dose is sufficient to prevent or reduce the effects of vascular stroke or other neurodegenerative diseases.
  • An exemplary daily dosage unit for a vertebrate host comprises an amount of from about 0.001 mg/kg to about 50 mg/kg.
  • NO-toxicitv bv PARP Inhibitors Primary cortical cell cultures were prepared from gestational, 16-day fetal mice in a procedure modified from that described in Dawson et al., "Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide Synthase Deficient Mice", J. Neurosci., 76:2479-87 (1996), the disclosure of which is hereby incorporated by reference.
  • the cortex was dissected, and the cortical cells were dissociated by a 30-minute digestion in 0.027% trypsin/saline solution (commercially available from Gibco BRL, Gaithersburg, MD), followed by trituration in modified Eagle's medium (MEM), 20% horse serum, 25 mM glucose and 2 mM L-glutamine.
  • MEM modified Eagle's medium
  • the cells were plated on 15 mm multi-well plates coated with polyornithine. Four days after plating, the cells were treated with 5-fluoro-2- deoxyuridine for three days to inhibit the proliferation of non-neuronal cells.
  • the cells were then maintained in MEM, 10% horse serum, 25 mM glucose, and 2 mM L-glutamine in an 8% CO 2 , humidified 37°C incubator.
  • the growth medium was refreshed twice per week, and the neurons were allowed to mature for 14 days in culture before being used for experiments. Mature levels of nNOS neurons, corresponding to 1-2% of the total neuronal population,
  • Figure 1 shows the PARP inhibitor BZD as triangles and DPQ as circles, as they inhibited toxicity induced by a five-minute exposure to 500 ⁇ M NMDA (open symbols) or 500 ⁇ M sodium nitroprusside (SNP) (closed symbols) in a dose- dependent manner.
  • the non-selective inhibitor benzamide provided protection against NMDA- or NO-induced neurotoxicity with an EC K , of about 100 ⁇ M.
  • DPQ was significantly more potent, providing 50% of maximal protection at 0.2 ⁇ M.
  • concentrations of 10-100 ⁇ M DPQ virtually abolished neurotoxicity, while the maximally effective concentration of benzamide only reduced neurotoxicity by 65%. Therefore, the non-selective PARP inhibitor benzamide was 500 times less potent than the selective PARP inhibitor DPQ. Said another way, DPQ was 500 times more potent than benzamide and abolished neurotoxicity at maximal doses.
  • PARP- - generated by the method of Wang et al., "Mice Lacking ADPRT and poly(ADP-ribosyl)ation Develop Normally But Are Susceptible to Skin Disease", Genes Dev., 9:509-20 (1995), which is hereby incorporated by reference.
  • EBSS glucose-free Earle's balanced salt solution
  • Toxicity was assayed 20-24 hours after exposure to cytotoxic conditions by microscopic examination with computer-assisted cell counting, following staining of all nuclei with 1 ⁇ g/ml Hoescht 33342 and staining of dead cell nuclei with 7 ⁇ g/ml propidium iodide. All reagents were purchased from Sigma Chemicals, St. Louis, MO.
  • the Fisher PLSD post-hoc test demonstrated differences at p ⁇ 0.0001 when comparing wild-type NMDA- or OGD-treated cultures to cultures with the addition of MK801 , NArg, BZD or DPQ, and differences at p ⁇ 0.0001 when comparing NMDA-treated cultures from PARP+/- to MK801 , NArg, BZD or DPQ treatments in the PARP+/- cultures (treatment).
  • Oxygen-glucose deprivation and NMDA-neurotoxicity in primary neuronal cultures was used to evaluate the extent of brain injury following middle cerebral artery occlusion (MCAo) in transgenic PARP+/- and PARP-/- mice, as compared with wild-type mice (129/SV, a strain of related 129 mice).
  • MCAo middle cerebral artery occlusion
  • mice Animal Care and Use Committee. The three groups of mice were subjected to two hours of MCAo, in which regional cerebral blood flow (rCBF) was decreased to approximately 30% of baseline, as shown in Figure 4.
  • rCBF regional cerebral blood flow
  • PARP-/- weighing 23-38 g were anesthetized with 1-1.2% halothane in oxygen- enriched air by face mask.
  • a laser-doppler probe was placed on the skull ipsilateral to the occlusion: 2 mm posterior and 3 mm lateral from the bregma.
  • the data for Figure 4 were analyzed by a one-way ANOVA with
  • the femoral arteries of the anesthetized mice were cannulated for measurement of arterial-blood gases and blood pressure. Rectal temperature was controlled at near 37°C throughout the experiment with heating lamps/water pads in all animals.
  • test animals were briefly re-anesthetized with halothane, and the filament was withdrawn through the external carotid artery, allowing reperfusion of the common and internal carotid arteries, but not the external carotid artery. After removal of the filament, rCBF immediately increased to 90- 110% of the baseline value.
  • MAPB is the mean arterial blood pressure in millimeters of mercury.
  • n 4.
  • Protein expression was determined by Western blot analysis, as follows: Fresh mouse brain was homogenized in 20% (w/v) 50 mM Tris-HCI (pH 7.4) buffer containing 1 mM EDTA, 1 mM dithiothreitol, 50 mM NaCl, 0.25 M sucrose, 0.2 mM PMSF, and 1 mg/ml of chymostatin, leupeptin, and pepstatin. The homogenate was centrifuged at 1000 g for 15 minutes at 4°C. The pellet, which contained the nuclear fraction, was then washed with the homogenizing buffer. The nuclear fraction was dissolved in SDS-PAGE sample buffer containing 4 M urea.
  • the mixture was subjected to extensive sonication, followed by boiling at 90°C for 15 minutes.
  • the PARP protein (200 ⁇ g) was separated on a gradient SDS-PAGE and identified by anti-PARP monoclonal antibody by the electron capture luminescence (ECL) method.
  • ECL electron capture luminescence
  • PARP activity was assessed using a self- modification assay method previously described by Zhang et al., "Nitric Oxide Activation of Poly(ADP-ribose) Synthetase in Neurotoxicity", Science, 263:687- 89 (1994), the disclosure of which is hereby incorporated by reference.
  • Fresh mouse brain tissues were homogenized in 20% (w/v) 50 mM Tris-CI (pH 7.4) buffer containing 1 mM EDTA, 1 mM dithiothreitol, 50 mM NaCl, 0.25 M sucrose, 0.2 mM PMSF, and 1 ⁇ g/ml of chymostatin, leupeptin and pepstatin.
  • the homogenate was centrifuged at 100 g for 15 minutes at 4°C.
  • the nuclear fraction referred to as the pellet, was then washed with the homogenizing buffer.
  • the washed pellet was re-suspended in the homogenizing buffer.
  • each 50 ⁇ l mixture contained 0.1 mM [adenylate- 32 P]NAD (10 Ci/mmol) (NEN, Life Sciences, Boston, MA).
  • PARP protein and catalytic activity were detected at modest levels in wild-type mouse forebrain.
  • PARP protein expression was markedly reduced from wild-type in the PARP+/- forebrain and was not detectable at all in the PARP-/- forebrain.
  • PARP catalytic activity was not detectable in the forebrains from either PARP+/- or PARP-/- mice.
  • the enzyme activity was probably reduced by at least 80% in the PARP+/- mice, despite a lesser depletion of PARP protein.
  • the marked reduction in PARP expression in PARP+/- mice may suggest that more than gene copy number affected the expression of PARP in the adult brain. Since PARP is involved in regulating the normal activity of numerous nuclear proteins, it is possible that the loss of a single PARP allele significantly affected the transcriptional elements that regulate the mature expression of PARP, resulting in lower than expected protein expression.
  • ADP-ribose polymer formation was examined as a marker of PARP catalytic activity. Following two hours of ischemia by MCAo and two hours of reperfusion, the brains of the test animals were rapidly removed and flash frozen. To detect poly(ADP-ribose) synthase activation, 15 ⁇ m thick sections from the freshly frozen brains were incubated in 200 ⁇ M NAD at 37°C for 45 minutes with modifications from the procedure taught by Kupper et al., "Detection of Poly(ADP-ribose) Polymerase and its Reaction Product
  • mice were fixed in 95% ethanol at -20°C for ten minutes and incubated overnight with mouse anti-poly(ADP-ribose) monoclonal antibody (available from BIOMOL Research Laboratories, Plymouth Meeting, PA) at a
  • Diaminobenzidine was used as a chromogen (Gibco BRL, Gaithersburg, MD).
  • ADP-ribose polymer formation as identified by immunohistochemistry, but there was minimal nuclear staining in the contralateral hemisphere of the same animal. In contrast, following the same two hours of MCAo and two hours of reperfusion in the PARP-/- animals, there was a complete absence of any ADP- ribose polymer staining in either the ipsilateral or the contralateral cortical hemisphere.

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Abstract

L'invention traite d'un procédé de prévention des dommages infligés aux tissus neuronaux par ischémie et lésion due à des perfusions répétées chez un mammifère. Ce procédé consiste à administrer à un mammifère une quantité efficace du point de vue thérapeutique d'un inhibiteur sélectif de la poly(ADP-ribose)polymérase (PARP). Selon un mode de réalisation préféré, cet inhibiteur sélectif est une isoquinolinone.
PCT/US1998/016959 1997-08-15 1998-08-14 Procede d'utilisation d'inhibiteurs selectifs de parp pour prevenir ou traiter la neurotoxicite WO1999008680A1 (fr)

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US6664269B2 (en) 2001-05-08 2003-12-16 Maybridge Plc Isoquinolinone derivatives
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US8129380B2 (en) 2008-01-23 2012-03-06 Astrazeneca Ab Phthalazinone derivatives
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US8859562B2 (en) * 2003-07-25 2014-10-14 The University Of Sheffield Use of RNAI inhibiting PARP activity for the manufacture of a medicament for the treatment of cancer
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5587384A (en) * 1994-02-04 1996-12-24 The Johns Hopkins University Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5587384A (en) * 1994-02-04 1996-12-24 The Johns Hopkins University Inhibitors of poly(ADP-ribose) synthetase and use thereof to treat NMDA neurotoxicity

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US8912187B2 (en) 2003-03-12 2014-12-16 Kudos Pharmaceuticals Limited Phthalazinone derivatives
US8859562B2 (en) * 2003-07-25 2014-10-14 The University Of Sheffield Use of RNAI inhibiting PARP activity for the manufacture of a medicament for the treatment of cancer
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US7902193B2 (en) 2005-10-19 2011-03-08 Maybridge Limited Phthalazinone derivatives
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