WO2002003993A2 - Use of inhibitors to multidrug resistance protein 5 (mrp5) to enhance intracellular levels of cyclic nucleotides - Google Patents
Use of inhibitors to multidrug resistance protein 5 (mrp5) to enhance intracellular levels of cyclic nucleotides Download PDFInfo
- 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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- WIPO (PCT)
- Prior art keywords
- mrp5
- inhibitor
- cgmp
- transport
- cells
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Classifications
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- 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
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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
- 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
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- 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
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- 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
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- 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
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- 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.
Landscapes
- 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)
- Epidemiology (AREA)
- 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)
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 |
|---|---|---|---|
| DE10033880.1 | 2000-07-12 | ||
| DE2000133880 DE10033880A1 (de) | 2000-07-12 | 2000-07-12 | Inhibierung von Multidrug-Resistenzprotein 5 (MRP5) zur Erhöhung der intrazellulären Niveaus zyklischer Nukleotide |
| US24697700P | 2000-11-13 | 2000-11-13 | |
| US60/246,977 | 2000-11-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002003993A2 true WO2002003993A2 (en) | 2002-01-17 |
| WO2002003993A3 WO2002003993A3 (en) | 2002-08-08 |
Family
ID=26006360
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2001/008077 WO2002003993A2 (en) | 2000-07-12 | 2001-07-12 | Use of inhibitors to multidrug resistance protein 5 (mrp5) to enhance intracellular levels of cyclic nucleotides |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2001276403A1 (ko) |
| WO (1) | WO2002003993A2 (ko) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005044244A3 (de) * | 2003-11-07 | 2006-10-05 | Univ Ernst Moritz Arndt | Verwendung von mrp4-inhibitoren zur behandlung und/oder prophylaxe kardiovaskulärer erkrankungen |
| 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)
| 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 |
-
2001
- 2001-07-12 AU AU2001276403A patent/AU2001276403A1/en not_active Abandoned
- 2001-07-12 WO PCT/EP2001/008077 patent/WO2002003993A2/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005044244A3 (de) * | 2003-11-07 | 2006-10-05 | Univ Ernst Moritz Arndt | Verwendung von mrp4-inhibitoren zur behandlung und/oder prophylaxe kardiovaskulärer erkrankungen |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2001276403A1 (en) | 2002-01-21 |
| WO2002003993A3 (en) | 2002-08-08 |
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