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WO2002003993A2 - Utilisation des inhibiteurs de la proteine 5 de resistance multidrogue (mrp) pour elever les taux intracellulaires de nucleotides cycliques - Google Patents

Utilisation des inhibiteurs de la proteine 5 de resistance multidrogue (mrp) pour elever les taux intracellulaires de nucleotides cycliques Download PDF

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Publication number
WO2002003993A2
WO2002003993A2 PCT/EP2001/008077 EP0108077W WO0203993A2 WO 2002003993 A2 WO2002003993 A2 WO 2002003993A2 EP 0108077 W EP0108077 W EP 0108077W WO 0203993 A2 WO0203993 A2 WO 0203993A2
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WO
WIPO (PCT)
Prior art keywords
mrp5
inhibitor
cgmp
transport
cells
Prior art date
Application number
PCT/EP2001/008077
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English (en)
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WO2002003993A3 (fr
Inventor
Gabriele Jedlitschky
Dietrich Keppler
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Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
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
Priority claimed from DE2000133880 external-priority patent/DE10033880A1/de
Application filed by Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts filed Critical Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
Priority to AU2001276403A priority Critical patent/AU2001276403A1/en
Publication of WO2002003993A2 publication Critical patent/WO2002003993A2/fr
Publication of WO2002003993A3 publication Critical patent/WO2002003993A3/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
    • A61K31/70—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
    • 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
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/365—Lactones
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention hinges on the surprising discovery that the
  • MRP5 gene symbol A CC5 transports
  • cyclic nucleotides such as cyclic 3',5'-
  • cGMP guanosine monophosphate
  • the present invention relates to the use of MRP5
  • inhibitors to treat or prevent pathophysiological conditions or diseases.
  • the invention relates to a method for enhancing the intracellular
  • cyclic nucleotides in particular cGMP, to treat or prevent conditions or diseases such as bronchial asthma, coronary disease, angina pectoris arterial
  • Lipid membranes are virtually impermeable to cyclic nucleotides, but
  • Cyclic adenosine monophosphate is a ubiquitous second
  • Some hormone-induced cellular responses mediated by cAMP include thyroid
  • Cyclic guanosine monophosphate is another cyclic nucleotide
  • cGMP is known to activate G-kinase which
  • extracellular cAMP acts as a
  • a second means of removing excess intracellular cyclic nucleotides involves
  • cyclic AMP phosphodiesterase hydrolyzes
  • MRP multidrug resistance protein
  • cMRP multidrug resistance protein
  • MRP3, MRP4, and MRP5 were mainly based on expressed
  • MRP5 has been shown to be ubiquitously expressed with high transcript
  • MRP5 may be a
  • nucleotides such as cGMP.
  • Enhancing the intracellular levels of cyclic nucleotides in a host can play
  • resistance protein isoform MRP5 (gene symbol ABCC5).
  • phosphodiesterase modulators including trequinsin, with a K t of 240 nM, and
  • MRP5 represents a novel
  • nucleotides such as cGMP.
  • MRP5 in combination with an inhibitor to phosphodiesterases.
  • test drugs or compounds to improve tissue specificity comprises comparing the tissue specific expression of MRP5 and phosphodiesterases and
  • triggering apoptosis in tumor cells comprising administering to a host a
  • MRP5 an in vector-transfected (V79-Co) or parental (V79) control cells.
  • RNA (30 ⁇ g) was hybridized under high stringency conditions (Hybridization
  • the blot was immuostained using the AMF antiserum detecting both the
  • Example V The substrate concentration at half-maximal velocity of transport
  • sGC soluble guanylyl cyclases
  • PDE 3',5'-cyclic nucleotide phosphodiesterases
  • downstream transduction pathways include cGMP-dependent protein
  • trequinsin, and zaprinast can enhance intracellular cGMP concentrations by a
  • extracelluar space may function, in addition, in cell-cell cross talk.
  • Hfist- A host includes humans, non-human primates, non-human
  • mammals and ungulates.
  • agricultural animals are especially included.
  • domestic animals such as dogs and cats.
  • the method for enhancing the intracellular levels of cyclic nucleotides.
  • composition comprising an inhibitor to both MRP5 and phosphodiesterase or a composition comprising an inhibitor to MRP5 in combination with an inhibitor
  • cyclic nucleotides in particular cyclic GMP.
  • an inhibitor to MRP5 and/or to phosphodiesterase can be any inhibitor to MRP5 and/or to phosphodiesterase.
  • an inhibitor of the invention is administered to a patient in need of treatment.
  • the dose of the inhibitor to be administered can be determined by methods well
  • the ixihibitor will prevent the transport of cyclic
  • nucleotides from cells thus, allowing for the enhancement of intracellular
  • cyclic nucleotides in particular cGMP.
  • cGMP include but are not limited to pathophysiological conditions, such as
  • inhibitor it is meant a compound or protein that reduces or
  • Inhibitors to MRP5 include but are not limited to fluorescein
  • an inhibitor is a compound or
  • mhibitors to phosphodiesterase include
  • Preferred mhibitors of the invention are inhibitors that have a dual
  • inhibitors to MRP5 that do not have a dual function can be used
  • cyclic nucleotides include, but are not
  • a monoclonal antibody a mixture of monoclonal antibodies
  • polyclonal antibodies a mixture of polyclonal antibodies, or a mixture of
  • Preferred antibodies include anti-MRP5 or anti-phosphodiesterase antibodies produced, for example, in rabbits, mice,
  • a human anti-MRP5 or anti-phosphodiesterase More preferably, a human anti-MRP5 or anti-phosphodiesterase
  • antibody a humanized anti-antibody, or an anti-MRP5 or anti-
  • humanized antibody it is meant an antibody which is less
  • the inhibitor composition of the invention may be administered to a
  • inhibitor compositions of the invention can be any suitable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable pharmaceutically acceptable carrier.
  • Such inhibitor compositions of the invention can be any suitable pharmaceutically acceptable pharmaceutically acceptable carrier.
  • parenteral may be oral, parenteral, by inhalation or topical. " The term parenteral as used
  • herein includes intravenous, intraperitoneal, intramuscular, subcutaneous, rectal
  • compounds of the invention will generally be in the range of about 0.05 to 100,
  • inhibitor compositions of the invention may also be administered by
  • inhalation intranasal and oral inhalation
  • aerosol formulation or a metered dose inhaler may be prepared by conventional techniques.
  • the inhibitor composition of the invention may also be administered
  • topical administration is meant non-systemic administration and
  • systemic administration is meant oral, intravenous, intraperitoneal and
  • the method comprises comparing the tissue specific expressions of MRP5 and
  • chemotherapeutic drugs such as anti-viral and anti-tumor drugs are rapidly
  • apoptosis in tumor cells comprising administering to a host a therapeutically
  • McAleer et al. J. Biol. Chem. 274: 23541-
  • SMRP truncated MRP5
  • cDNA in the expression vector was assessed by restriction analysis and
  • RNA (30 ⁇ g), isolated from transfected cells using the RNeasy kit
  • MRP5 cD ⁇ A or a ⁇ -actin control probe were used for detection.
  • Membranes were hybridized and washed with high stringency as described (Jedhtschky et
  • Membrane fractions were diluted with sample buffer und incubated at
  • Immunoblotting was performed using a tank blotting system (Bio-Rad) and an
  • Plasma membrane vesicles from transfected V79 cells were prepared
  • K m values were determined as substrate concentration at half-maximal
  • Human MRP5 cDNA was cloned from a human brain cDNA library and
  • V79-MRP5 Chinese hamster
  • RNA level by Northern blotting (Fig. 1 A) performed on total RNA isolated
  • membrane vesicles (Membranes) using the polyclonal antibody AMF directed
  • erythrocytes indicating the expression of MRP5 in red blood cells (Fig. IC).
  • the antibody showed no cross-reactivity with human MRP1, MRP2, MRP3, or
  • n 3) of the value obtained under standard conditions with 250 mM sucrose.
  • V79-MRP5 vesicles This transport was below the detection limit with
  • This anionic fluorescent dye had been identified as an MRP5 substrate in
  • Membrane vesicles from V79-MRP5 cells were incubated with [ 3 H]cGMP (1 ⁇ M) for 15 min at 37°C in the presence of several amphiphihc anions and compounds known as phosphodiesterase inhibitors at the concentrations indicated. Rates of ATP-dependent [ 3 H]cGMP transport were determined as described in the legend to Fig. 1 and calculated as % of control. The control [ 3 H]cGMP transport in these experiments was 16.2 ⁇ 2.2 pmol x mg protein " ' at 15 min. Data represent mean values ⁇ S.D. from three determinations. EXAMPLE IX
  • leukotriene C 4 could be detected in incubations with [ 3 H]leukotriene C 4 in
  • nucleotides 8-bromo-cGMP, N 2 ,2'-0-dibutyryl-cGMP, the phosphodiesterase
  • the AMF antibody was raised in rabbits against the 14 carboxyl-
  • Cyclic GMP has emerged as a major focus in signal transduction
  • cellular cGMP levels are determined by the rate of
  • Elimination pathways comprise degradation by phosphodiesterases, as well as
  • vesicles from human erythrocytes suggested that cGMP is transported by an
  • MRP5-mediated cAMP transport may only be significant under conditions with high intracellular cAMP levels.
  • lymphoid CEM-rl cells resistant to nucleoside-based antiviral drugs resistant to nucleoside-based antiviral drugs, and an
  • kidney cells has been reported (Wijnholds et al., Proc. Natl. Acad. Set U.S.A.
  • the present application identifies for the first time natural cyclic
  • nucleotides as substrates of an ATP-binding cassette transporter of the MRP
  • cGMP and cAMP are also the first phosphate substrates for which
  • MRP4 may function as transporters for cyclic nucleotides, as well.
  • this transporter may be
  • these compounds can enhance intracellular cGMP levels through a dual phosphodiesterase inhibitors, including sildenafil as the most prominent one.
  • sildenafil as the most prominent one.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé pour augmenter les taux intracellulaires de nucléotides cycliques et notamment de monophosphate de guanosine cyclique (cGMP). Le procédé consiste à administrer à un hôte une quantité thérapeutiquement efficace d'un inhibiteur de MRP5 et de phosphodiestérase ou administrer un inhibiteur à MRP5 en combinaison avec un inhibiteur de phosphodiestérases. L'invention concerne aussi des procédés pour identifier les inhibiteurs de MRP5 pour traiter les états dans lesquels on désire des taux intracellulaires de cGMP plus élevées ou pour traiter la résistance multidrogue à médiation par MRP5.
PCT/EP2001/008077 2000-07-12 2001-07-12 Utilisation des inhibiteurs de la proteine 5 de resistance multidrogue (mrp) pour elever les taux intracellulaires de nucleotides cycliques WO2002003993A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001276403A AU2001276403A1 (en) 2000-07-12 2001-07-12 Use of inhibitors to multidrug resistance protein 5 (mrp5) to enhance intracellular levels of cyclic nucleotides

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE2000133880 DE10033880A1 (de) 2000-07-12 2000-07-12 Inhibierung von Multidrug-Resistenzprotein 5 (MRP5) zur Erhöhung der intrazellulären Niveaus zyklischer Nukleotide
DE10033880.1 2000-07-12
US24697700P 2000-11-13 2000-11-13
US60/246,977 2000-11-13

Publications (2)

Publication Number Publication Date
WO2002003993A2 true WO2002003993A2 (fr) 2002-01-17
WO2002003993A3 WO2002003993A3 (fr) 2002-08-08

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Country Status (2)

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WO (1) WO2002003993A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044244A3 (fr) * 2003-11-07 2006-10-05 Univ Ernst Moritz Arndt Utilisation d'inhibiteurs de mrp4 pour assurer le traitement et/ou la prophylaxie de maladies cardio-vasculaires
CN118324864A (zh) * 2024-04-30 2024-07-12 南方科技大学 靶向人源多药耐药相关蛋白mrp5的肽类抑制剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9301192D0 (en) * 1993-06-09 1993-06-09 Trott Francis W Flower shaped mechanised table
US6201028B1 (en) * 1998-12-08 2001-03-13 The Rockefeller University Methods and compositions for prevention and treatment of atherosclerosis and hyperlipidemia with non-steroidal anti-inflammatory drugs
DE10004289A1 (de) * 2000-02-01 2001-08-02 Stief Christian Behandlungen von Sexualfunktionsstörungen mit Phosphodiesterase 4-Hemmern als Monotherapie oder in Kombination mit anderen Phosphodiesterase-Hemmern oder Stimulatoren der Adenylat-Zyklase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005044244A3 (fr) * 2003-11-07 2006-10-05 Univ Ernst Moritz Arndt Utilisation d'inhibiteurs de mrp4 pour assurer le traitement et/ou la prophylaxie de maladies cardio-vasculaires
CN118324864A (zh) * 2024-04-30 2024-07-12 南方科技大学 靶向人源多药耐药相关蛋白mrp5的肽类抑制剂

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WO2002003993A3 (fr) 2002-08-08
AU2001276403A1 (en) 2002-01-21

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