WO1999061024A1 - Ligands de recepteurs peripherique de la benzodiazepine - Google Patents

Ligands de recepteurs peripherique de la benzodiazepine Download PDF

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Publication number
WO1999061024A1
WO1999061024A1 PCT/CA1998/000502 CA9800502W WO9961024A1 WO 1999061024 A1 WO1999061024 A1 WO 1999061024A1 CA 9800502 W CA9800502 W CA 9800502W WO 9961024 A1 WO9961024 A1 WO 9961024A1
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WIPO (PCT)
Prior art keywords
compound
compounds
inflammatory condition
peripheral benzodiazepine
benzodiazepine receptors
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Application number
PCT/CA1998/000502
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English (en)
Inventor
Patrick L. Mcgeer
J. Douglas Waterfield
Edith G. Mcgeer
Andis Klegeris
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The University Of British Columbia
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of British Columbia filed Critical The University Of British Columbia
Priority to EP98922551A priority Critical patent/EP1077702A1/fr
Priority to JP2000550484A priority patent/JP2002516279A/ja
Priority to CA002332825A priority patent/CA2332825A1/fr
Priority to PCT/CA1998/000502 priority patent/WO1999061024A1/fr
Priority to AU75168/98A priority patent/AU7516898A/en
Publication of WO1999061024A1 publication Critical patent/WO1999061024A1/fr

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention pertains to the use of compounds which bind with high affinity to peripheral benzodiazepine receptors as antii___fla____matory agents.
  • Such compounds include isoquinoline and benzodiazepine derivatives. These compounds may be used in the treatment of human diseases such as rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, osteoarthritis, multiple sclerosis, Behcet's disease, temporal aretritis and dementia of the Alzheimer type.
  • Benzodiazepine receptors Two broad classes of benzodiazepine receptors have been described: central and peripheral.
  • Ligands for central benzodiazepine receptors such as diazepam, flunitrazepan and clonazepam, produce an interaction with GABA A receptors, enhancing the activity of GABA (gamma-aminobutyric acid).
  • GABA gamma-aminobutyric acid
  • These ligands possess anticonvulsant, muscle relaxant, sedative and anxiolytic properties. They are widely used clinically.
  • the receptors are highly concentrated in brain, but are also found peripherally.
  • Ligands that are selective for peripheral benzodiazepine receptors such as 4'- chlorodiazepam (Ro 5-4864) and l-(2-chlorophenyl)-N-methyl-N-(l-methylpropyl)-3- isoquinolinecarboxamide (PK 11195), do not interact with GABA receptors and do not possess the same pharmacological properties as the central benzodiazepine receptor ligands. Instead they bind to peripheral benzodiazepine receptors which are widely distributed throughout the body, including the central nervous system.
  • the peripheral benzodiazepine receptor ligands have no well defined pharmacological properties, and so far there are no generally aceepted clinical applications for their use.
  • peripheral benzodiazepeine receptors means the class of peripheral benzodiazepine receptors as distinguished from the class of central benzodiazepine receptors
  • peripheral benzodiazepine receptor ligands means ligands that bind with high affinity to peripheral benzodiazepine receptors.
  • PK 11195 has a particularly high affinity for peripheral benzodiazepine receptors.
  • the equilibrium dissociation constant, or affinity (Kd) of PK 11195 for human brain tissue is estimated to be 4.3 nM ⁇ Doble et al., 1987). Its affinity for mouse peritoneal macrophages is reported to be 5.6 nM (Zavala andLieri, 1987b).
  • Ki peripheral benzodiazepine receptors
  • PK 11195 has been shown to inhibit in vitro mitogen-driven T- and B- cell stimulation, properties shared by a number of central benzodiazepine ligands (Ramseir et al. , 1993; Bessler et al. , 1992). In contrast, PK 11195 has also been reported to stimulate antibody production in mice following immunization with sheep red blood cells (Lieri and Zavala, 1986; Zavala et al., 1984; Zavala and Lieri, 1987b) which would enhance the inflammatory response.
  • Peripheral benzodiazepine receptor ligands including Ro 5-4864, have also been reported to enhance the respiratory burst system of macrophage-like P388D1 cells stimulated with arachidonic acid.
  • PK 11195 in the same situation reportedly had little effect (Zavala and lieri, 1987a).
  • peripheral benzodiazepine receptors are believed to be associated with glial cells. However, it is not clear what the physiological function of these receptors in brain might be.
  • Various authors have reported increases in peripheral benzodiazepine receptor levels in rat brain following kainic acid, ischemic, or neoplastic lesions. Similar findings have been reported for human brain tissue in patients with brain tumours, neoplasms, multiple sclerosis, cerebrovascular disorders and Alzheimer's disease. The teaching is that these increases in peripheral benzodiazepine receptor levels reflect glial proliferation (Diorio et al., 1991; Leong et al, 1994).
  • the invention discloses that ligands which bind with high affinity to peripheral benzodiazepine receptors act as antiinflammatory agents.
  • a method of treating an inflammatory condition in a mammal comprises administering to a mammal requiring such treatment a therapeutically effective amount of a compound which binds with high affinity to peripheral benzodiazepine receptors. This may require dosages in the range of 0.1-100 mg/kilogram of body mass per day or roughly (0.3-320 micromoles/kilogram per day depending on the molecular weight of the agent), as determined by a medical practitioner or veterinarian.
  • the compound is selected from the group consisting of compounds which bind with micromolar or submicromolar affinity to peripheral benzodiazepine receptors, as, for example, PK 11195 or pharmacologically acceptable salts thereof.
  • compositions comprising a peripheral benzodiazepine receptor ligand in combination with one or more compatible pharmaceutically acceptable adjuvents or diluents which may be inert or physiologically active. These compositions may be administered by the oral, parenteral or rectal route or locally.
  • Compositions of the invention comprising a peripheral benzodiazepine receptor ligand may be packaged in packaging material that comprises a label which indicates that the composition can be used for treating inflammatory conditions.
  • the present invention provides a method of identifying a compound that is therapeutically effective for treating an inflammatory condition in a mammal.
  • the method comprises selecting a compound: ( 1 ) that binds with micromolar or submicromolar affinity to peripheral benzodiazepine receptors; and (2) that is therapeutically effective in treating inflammatory symptoms in MRL-lpr mice. Additional steps that may be taken in the method of indentifying an antiinflammatory compound include:
  • the compound utilized in the various aspects of the invention may be selected from the group consisting of: PK 11195, PK-14067, PK 14105, Ro 5-6993, Ro 5-4864, Ro 5-6900, Ro 5-6945, Ro 5-6669, Ro 5-6902, Ro 5-6531, Ro 5-3448,
  • the compound is preferably l-(2-chlorophenyl)-N-methyl-N-(l-methylpropyl)-3- isoquinolinecarboxamide (PK 11195).
  • This invention discloses the use of high affinity peripheral benzodiazepine receptor ligands as a new class of antiinflammatory compounds.
  • This class of compounds includes isolquinoline drivatives such as PK 11195 and benzodiazepine derivatives such as Ro 5-4864.
  • the following examples illustrate various aspects of this invention, including four assays for defining the antiinflammatory pharmacological profile of such drugs. These assays establish the utility of high affinity peripheral benzodiazepine receptor ligands as antiinflammatory agents on the basis of the following results:
  • Pronounced therapeutic activity in the MRL-lpr mouse autoimmune disease is an accepted model of a variety of human diseases: rheumatoid arthritis (Koopman and Gay, 1988), systemic lupus erythematosus (Bartlett et al, 1988), Sjogren's syndrome (Hayashi et al, 1994), connective tissue disease (Rosenberg, 1988), behavioral and neurological disorders (Sakic et al, 1993) and CNS inflammation (Vogelweid et al, 1991).
  • PK 11195 demonstrated a more powerful prevention of pathology in this autoimmune disorder than standard antiinflammatory agents.
  • PK 11195 was a more potent down regulator than standard antiinflammatory agents.
  • Alzheimer disease tissue is a model for inflammatory disease of the central nervous system.
  • PK 11195 and Ro 5-4864 showed greater high affinity binding to Alzheimer brain tissue than to neurologically normal brain tissue, with the difference being greater for PK 11195.
  • peripheral benzodiazepine receptor ligands in the treatment of animal and human disorders of an inflammatory nature. These include, but are not limited to, rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, osteroarthritis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, myasthenia gravis, temporal arteritis, Hashimoto's disease, dermatitis herpetiformis and other diseases, including Alzheimer disease, where chronic inflammation may exacerbate the fundamental pathology (as discussed in more detail below).
  • MLR-lpr mice are a widely studied strain which spontaneously develop a particularly severe autoimmune disorder. Pathologies that are found in a variety of human idiopathic inflammatory and autoimmune diseases are reproduced in these animals. They are therefore considered to be an outstanding model for such individual human diseases, although the pathology represents a combination of several of them. They are regarded as the best animal model for rheumatoid arthritis (Koopman and Gay, 1988), systemic lupus erythematosus (Bartlett et al, 1988), and Sjogren's syndrome (Hayashi et al, 1994).
  • the lesions include synovial inflammation, synovial cell proliferation, pannus formation, and articular cartilage erosion and bone destruction. Only powerful antiinflammatory agents will inhibit the devastating changes that accompany this genetic disorder.
  • Mice of the MRL-lpr strain spontaneously develop a mild form of the disease at 4 to 5 months of age. The onset and severity can be accelerated by injection of complete Freund's adjuvant (CFA), supplemented to 10 mg/ml with heat-inactivated M. tuberculosis, at 13-14 weeks of age, with 67-82% of animals becoming affected within 1 month (Ratkay et al, 1994; Ratkay et al, 1993).
  • CFA complete Freund's adjuvant
  • mice of the MRL-lpr strain were injected at 13-14 weeks of age with 0.05 ml of CFA supplemented to 10 mg/ml with heat- inactivated M. tuberculosis at each of two intradermal thoracic sites according to the standard procedure, and, following injection (day 0), were started on a daily subcutaneous dose of PK 11195 dissolved in alcohol. Daily injections were continued until day 14. The animals were sacrificed at day 30 and joint histopathology assessed.
  • PK 11195 at the 0.1 mg/kg dose, was more effective than ten times that dose of indomethacin, forty times that of cyclosporin, and whole body irradiation at 3 Gy from a 60 cobalt source on day 1 of arthritis injection.
  • Table 1 Inhibition of CFA-induced disease in MRL-lpr mice by PK 11195 in Ethanol (Mean ⁇ S.D.)
  • A The histopathological changes were assessed on a scale of 0 (no change) to 4 (severe change) for the following indices: (1) subsynovial inflammation; (2) synovial hyperplasia; (3) pannus formation; and (4) bone destruction. For methods see Ratkay et al, 1994.
  • DMSO dimethyl sulf oxide
  • About 80% of the non-treated animals developed visibly arthritic joints.
  • A The histopathological changes were assessed on a scale of 0 (no change) to 4 (severe change) for the following indices: (1) subsynovial inflammation; (2) synovial hyperplasia; (3) pannus formation; and (4) bone destruction. For methods see Ratkay et al, 1994.
  • PK 11195 has a preventative effect against the induction of arthritis in the well established MRL-lpr animal model.
  • PK 11195 at 3.0 mg/kg significantly reduced the swelling (Table 3). This was confirmed by histological analyses following sacrifice at day 30.
  • A The histopathological changes were assessed on a scale of 0 (no change) to 4 (severe change) for the following indices: (1) subsynovial inflammation; (2) synovial hyperplasia; (3) pannus formation; and (4) bone destruction. For methods see Ratkay et al, 1994.
  • the respiratory burst system is an attack mechanism possessed by professional phagocytes such as peritoneal macrophages. Its main function is to protect the body from hostile invaders by generating superoxide radicals, but inappropriate activation can damage host tissue. Oxidative stress is believed to be one of the more harmful concomitants of inflammation.
  • the respiratory burst system can be activated in cultured peritoneal macrophages in multiple ways, including exposure to zymosan particles opsonized by complement proteins (Klegeris and McGeer, 1994).
  • the ability of PK 11195 to inhibit respiratory burst by administra- tion before or after exposure of peritoneal macrophages to opsonized zymosan is shown in Table 5.
  • PK 11195 inhibited respiratory burst by more than 50% whether given before or after opsonized zymosan. This indicates that the effect was downstream from, or independent of, the opsonized zymosan receptors.
  • Table 5 also shows the comparative effects of three agents effective in inflammatory disorders: indomethacin, prednisone and dapsone. Each of these agents was substantially less effective than PK 11195, and tended to show less inhibition when administered after opsonized zymosan than before.
  • PK 11195 inhibits respiratory burst more powerfully and by different mechanisms than these well known antiinflammatory agents. It is also more effective than 4*-chlorodiazepam, the prototype benzodiazepine ligand for peripheral benzodiazepine receptors.
  • OZ# opsonized zymosan
  • EXAMPLE 3 Reduction of Cvtotoxicitv to Neuronal SY5Y Cells Caused bv Secretory Products of Monocvtic THP-1 Cells Stimulated bv Inflammatory Mediators
  • Cultured cells of the monocytic type such as THP-1 cells, when stimulated by inflammatory agents, secrete products which in their aggregate are toxic to cultured neurons.
  • Human monocytic THP-1 cells were plated in 24- well plates at a concentra- tion of 5xl0 5 cells per well in 1 ml of Dulbecco's Modified Eagle Medium Nutrient
  • THP-1 cells were incubated in the presence or absence of drugs for 30 minutes prior to the addition of an inflammatory stimulus consisting of l_ ⁇ g/ml lipopolysaccharide (LPS) with 333 U/ml of interferon-7 (IFN- ⁇ ). After 24 hours incubation in a humidified 5%CO 2 /95% air atmosphere at 37°C, 0.5 ml aliquots of cell-free supernatants were transferred to the wells containing SY5Y cells which had been plated 24 hours earlier. After 72 hours of culture, cell death was evaluated by the amount of lactate dehydrogenase (LDH) which had been released into the medium from lysed cells.
  • LPS lipopolysaccharide
  • IFN- ⁇ interferon-7
  • %lysed cells 100 x [ ⁇ A(treated)- ⁇ A(untreated)]/ ⁇ A(lysed) where ⁇ A is absorbance of supernatants at 490 nm from which background absorbance has been subtracted.
  • ⁇ A(treated) was the measurement on supernatant from drug-treated cells, ⁇ A(untreated) that from cells incubated only with fresh medium, and ⁇ A(lysed) that from cells where complete lysis was achieved with 1 % Triton X-100.
  • the MTT assay was perfomed as described by Mosmann (1983) and by Hansen et al. (1989). This method is based on the conversion of MTT to colored formazan by viable but not by dead cells.
  • the viability of SY5Y cells was determined by adding MTT to the SY5Y cell cultures to reach the final concentration of 1 mg/ml. Plates were placed overnight at 37 °C and optical densities at 570 nm were measured by transferring 100 ⁇ l aliquots to 96-well plates and using the plate reader with a corresponding filter. The percentage of viable cells was calculated by the following formula:
  • % viable cells 100 x [OD (treated)-OD(lysed)]/[OD(untreated)-OD(lysed)] where OD is the optical density.
  • treated refers to cells treated with drug, untreated to those incubated only with fresh medium, and lysed to those where complete lysis was achieved with 1 % Triton X-100.
  • a criterion by which the potency of other isoquinoline or benzodiazepine derivatives can be compared with PK 11195 is their ability to displace PK 11195 in a competitive binding assay (Doble et al. , 1987) .
  • EXAMPLE 5 A Method of Identifying Novel Antiinflammatory Compounds
  • the invention provides a method of identifying a compound that is therapeutically effective for treating an inflammatory condition in a mammal. The method comprises selecting a compound:
  • the compound utilized may be selected from the group consisting of: PK 11195, PK-14067, PK 14105, Ro 5-6993, Ro 5-4864, Ro 5-6900, Ro 5-6945, Ro 5-6669, Ro 5-6902, Ro 5-6531, Ro 5-3448, Diazepam, Ro 7-5520, Ro 5-5115, Ro 5-4608, Ro 5-6524, Ro 5-5122, therapeutically acceptable salts of these compounds or mixtures of these compounds or their salts.
  • a method of treating an inflammatory condition in a mammal comprises administering to a mammal requiring such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt of the compound, the compound being selected from the group consisting of compounds which bind with micromolar or submicromolar affinity to peripheral benzodiazepine receptors.
  • the method may be practiced where the mammal is a human being and the compound binds with micromolar or submicromolar affinity to human peripheral benzodiazepine receptors.
  • the inflammatory condition may be rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, osteoarthritis, multiple sclerosis, Behcet's disease, temporal arteritis, and, without being limited by the foregoing, any inflammatory disorder which calls for the use of antiinflammatory agents.
  • the inflammatory condition may be dementia of the Alzheimer type and the peripheral benzodiazepine receptors may be those that are found in brain. Dementia of the Alzheimer type is included in this category since it has been shown to be characterized by chronic inflammation of the brain and to respond to antiinflammatory therapy (U.S. Patent 5,192, 753; European patent 0 642 336 Bl).
  • a preferred compound is PK 11195.
  • the compound may be selected from the group consisting of: PK 11195, PK-14067, PK 14105, Ro 5-6993, Ro 5-4864, Ro 5-6900, Ro 5-6945, Ro 5-6669, Ro 5-6902, Ro 5-6531, Ro 5-3448, Diazepam, Ro 7-5520, Ro 5-5115, Ro 5-4608, Ro 5-6524, Ro 5-5122, therapeutically acceptable salts of these compounds or mixtures of these compounds or their salts, or other compounds that bind with as high or higher affinity to peripheral benzo- diazepine receptors.
  • the invention includes pharmaeutical compositions comprising a peripheral benzodiazepine receptor ligand in combination with one or more compatible pharmaceutically acceptable adjuvents or diluents which may be inert or physiologically active. These compositions may be administered by the oral, parenteral or rectal route or locally.
  • the peripheral benzodiazepine receptor ligand may be PK 11195.
  • the ligand may be selected from the group consisting of: PK 11195, PK-14067, PK 14105, Ro 5-6993, Ro 5-4864, Ro 5-6900, Ro 5-6945, Ro 5- 6669, Ro 5-6902, Ro 5-6531, Ro 5-3448, Diazepam, Ro 7-5520, Ro 5-5115, Ro 5- 4608, Ro 5-6524, Ro 5-5122, therapeutically acceptable salts of these compounds or mixtures of these compounds or their salts, or other compounds that bind with as high or higher affinity to peripheral benzodiazepine receptors.
  • Tablets, pills, powders (gelatin capsules or cachets) or granules may be used as solid compositions for oral administration.
  • the active ingredient according to the invention may be mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica.
  • these compositions may also contain substances other than diluents, for example one or more lubricants such as magnesium stearate or talcum, a colorant, a coating (dragees) or a lacquer.
  • compositions for oral administration may contain substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.
  • Sterile compositions for parenteral administration may preferably be non- aqueous solutions, suspensions or emulsions.
  • Water, ethanol, propylene glycol, polyethylene glycol, benzoic acid, benzyl alcohol, sodium benzoate, dimethyl sulf oxide, vegetable oils, especially olive oil, injectable organic acids esters, for example ethyl oleate or other suitable organic solvents may be used as the solvent or the carrier.
  • compositions may also contain adjuvants, especially wetting agents, tonicity regulating agents, emulsifiers, dispersants and stabilizers.
  • the sterilization may be carried out in several ways, for example by aseptic filtration, incorporating a sterilizing agent, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in a sterile medium suitable for injection.
  • compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
  • compositions for local administration may be for example creams, ointments, lotions, eye lotions, mouth- washes, nasal drops or aerosols.
  • the dosage depends on the effect sought, the length of treatment and the administration route employed. In general, the medical practitioner (or veterinarian) will determine the appropriate dosage depending on the age, weight and all other factors specific to the subject to be treated.
  • the approximate dosage range may be chosen from the dosage range shown to be effective in resisting damage in the MRL- lpr murine rheumatoid arthritis model, i.e. 0.1 mg/kg to 100 mg/kg, with the most probable range being 1-10 mg/kg body weight per day.
  • compositions of the invention comprising a peripheral benzodiazepine ligand may be packaged in packaging material that comprises a label which indicates that the composition can be used for treating inflammatory conditions.
  • Such conditions include rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, osteoarthritis, multiple sclerosis, Behcet's disease, temporal arteritis and dementia of the Alzheimer type.
  • the peripheral benzodiazepine receptor ligand of the composition preferably exhibits micromolar or submicromolar affinity to peripheral benzodiazepine receptors, for example PK 11195.
  • the ligand may be selected from the group consisting of: PK 11195, PK-14067, PK 14105, Ro 5-6993, Ro 5-4864, Ro 5-6900, Ro 5-6945, Ro 5- 6669, Ro 5-6902, Ro 5-6531, Ro 5-3448, Diazepam, Ro 7-5520, Ro 5-5115, Ro 5- 4608, Ro 5-6524, Ro 5-5122, therapeutically acceptable salts of these compounds or mixtures of these compounds or their salts, or other compounds that bind with as high or higher affinity to peripheral benzodiazepine receptors.
  • Taupin, V. , Herbelin, A. , Descamps-Latscha, B., Zavala, F. Endogenous anxiogenic peptide, ODN-diazepam binding inhibitor, and benzodiazepines enhance the production of interleukin-1 and tumor necrosis factor by human monocytes. Lymphokine & Cytokine Res 1991;10:7-13.

Abstract

L'invention concerne des composés qui se lient avec forte affinité aux récepteurs périphériques de la benzodiazépine utiles comme agents anti-inflammatoires. Ces composés contiennent des dérivés d'isoquinoline, tels que PK 11195 et des dérivés de benzodiazépine, tels que Ro 5-4864. L'invention concerne également un procédé de traitement d'une maladie inflammatoire chez un mammifère à l'aide de ces composés et des compositions pharmaceutiques renfermant ces composés. Fait aussi l'objet de cette invention un procédé d'identification de composés thérapeutiquement efficaces pour le traitement des maladies inflammatoires.
PCT/CA1998/000502 1998-05-22 1998-05-22 Ligands de recepteurs peripherique de la benzodiazepine WO1999061024A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP98922551A EP1077702A1 (fr) 1998-05-22 1998-05-22 Ligands de recepteurs peripherique de la benzodiazepine
JP2000550484A JP2002516279A (ja) 1998-05-22 1998-05-22 末梢ベンゾヂアゼピンレセプターリガンド
CA002332825A CA2332825A1 (fr) 1998-05-22 1998-05-22 Ligands de recepteurs peripherique de la benzodiazepine
PCT/CA1998/000502 WO1999061024A1 (fr) 1998-05-22 1998-05-22 Ligands de recepteurs peripherique de la benzodiazepine
AU75168/98A AU7516898A (en) 1998-05-22 1998-05-22 Peripheral benzodiazepine receptor ligands

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Application Number Priority Date Filing Date Title
PCT/CA1998/000502 WO1999061024A1 (fr) 1998-05-22 1998-05-22 Ligands de recepteurs peripherique de la benzodiazepine

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009683A2 (fr) * 2000-07-27 2002-02-07 Pharmacia Corporation Therapie anti-aldosterones destinee a prevenir ou traiter les troubles lies a une inflammation
WO2003030937A1 (fr) * 2001-10-05 2003-04-17 Ono Pharmaceutical Co., Ltd. Remedes contre des maladies liees au stress comprenant des antagonistes de recepteurs mithochondriaux de la benzodiazepine
US7851485B2 (en) 2005-04-26 2010-12-14 Japan Science And Technology Agency Therapeutic agent for neuropathic pain

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091381A (en) * 1991-04-12 1992-02-25 Biomeasure, Inc. 2H-1,3,4-benzotriazepin-2-ones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5091381A (en) * 1991-04-12 1992-02-25 Biomeasure, Inc. 2H-1,3,4-benzotriazepin-2-ones

Non-Patent Citations (2)

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Title
C. FERRARESE ET AL.: "Peripheral benzodiazepine receptors and diazepam binding inhibitor in lymphocytes of demented patients.", ALZHEIMER'S RESEARCH, vol. 2, no. 4, 1996, pages 129 - 131, XP002094291 *
E. VOWINCKEL ET AL.: "PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis.", J. NEUROSCI. RES., vol. 50, no. 2, 1997, pages 345 - 353, XP002094292 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002009683A2 (fr) * 2000-07-27 2002-02-07 Pharmacia Corporation Therapie anti-aldosterones destinee a prevenir ou traiter les troubles lies a une inflammation
WO2002009683A3 (fr) * 2000-07-27 2003-09-12 Pharmacia Corp Therapie anti-aldosterones destinee a prevenir ou traiter les troubles lies a une inflammation
WO2003030937A1 (fr) * 2001-10-05 2003-04-17 Ono Pharmaceutical Co., Ltd. Remedes contre des maladies liees au stress comprenant des antagonistes de recepteurs mithochondriaux de la benzodiazepine
US7851485B2 (en) 2005-04-26 2010-12-14 Japan Science And Technology Agency Therapeutic agent for neuropathic pain

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EP1077702A1 (fr) 2001-02-28
CA2332825A1 (fr) 1999-12-02
AU7516898A (en) 1999-12-13

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