EP1448210A2 - REGULATION DER cGMP-SPEZIFISCHEN PHOSPHODIESTERASE 9A - Google Patents
REGULATION DER cGMP-SPEZIFISCHEN PHOSPHODIESTERASE 9AInfo
- Publication number
- EP1448210A2 EP1448210A2 EP02772410A EP02772410A EP1448210A2 EP 1448210 A2 EP1448210 A2 EP 1448210A2 EP 02772410 A EP02772410 A EP 02772410A EP 02772410 A EP02772410 A EP 02772410A EP 1448210 A2 EP1448210 A2 EP 1448210A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- pde9a
- prophylaxis
- cgmp
- inhibitors
- treatment
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 101001117259 Homo sapiens High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Proteins 0.000 title description 37
- 102100024227 High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A Human genes 0.000 title description 34
- 230000033228 biological regulation Effects 0.000 title description 4
- 229940122229 Phosphodiesterase 9A inhibitor Drugs 0.000 claims abstract description 15
- 238000011321 prophylaxis Methods 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 206010019280 Heart failures Diseases 0.000 claims abstract description 6
- 208000029078 coronary artery disease Diseases 0.000 claims abstract description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 5
- 208000007718 Stable Angina Diseases 0.000 claims abstract description 5
- 206010049418 Sudden Cardiac Death Diseases 0.000 claims abstract description 5
- 208000007814 Unstable Angina Diseases 0.000 claims abstract description 5
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 5
- 206010020772 Hypertension Diseases 0.000 claims abstract description 4
- 206010000891 acute myocardial infarction Diseases 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 abstract description 2
- 206010003210 Arteriosclerosis Diseases 0.000 abstract 1
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract 1
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 16
- 210000004351 coronary vessel Anatomy 0.000 description 12
- 210000002216 heart Anatomy 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 230000003834 intracellular effect Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000003752 polymerase chain reaction Methods 0.000 description 7
- 101000988412 Homo sapiens cGMP-specific 3',5'-cyclic phosphodiesterase Proteins 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 102000053871 human PDE9A Human genes 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- 108091093088 Amplicon Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 2
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000010804 cDNA synthesis Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000916 dilatatory effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000036284 oxygen consumption Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- COCMHKNAGZHBDZ-UHFFFAOYSA-N 4-carboxy-3-[3-(dimethylamino)-6-dimethylazaniumylidenexanthen-9-yl]benzoate Chemical compound C=12C=CC(=[N+](C)C)C=C2OC2=CC(N(C)C)=CC=C2C=1C1=CC(C([O-])=O)=CC=C1C(O)=O COCMHKNAGZHBDZ-UHFFFAOYSA-N 0.000 description 1
- BZTDTCNHAFUJOG-UHFFFAOYSA-N 6-carboxyfluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(C(=O)O)C=C21 BZTDTCNHAFUJOG-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 101150098694 PDE5A gene Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 108010010677 Phosphodiesterase I Proteins 0.000 description 1
- 108010006785 Taq Polymerase Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000010805 cDNA synthesis kit Methods 0.000 description 1
- 230000003222 cGMP degradation Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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 invention relates to the use of PDE9A inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of coronary heart diseases, in particular stable and unstable angina pectoris, acute myocardial infarction, myocardial infarction prophylaxis, sudden cardiac death, heart failure, and high blood pressure and the consequences of atherosclerosis.
- the heart as a continuously working hollow muscle, needs a particularly intensive supply of oxygen to cover its energy needs.
- Supply disorders therefore primarily concern oxygen transport, which can be insufficient if the blood circulation is less adaptable.
- An increase in oxygen consumption can only be covered by an increase in cardiac blood flow.
- the effects described above can be controlled via the intracellular concentration of the so-called “second messenger” cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).
- cAMP cyclic adenosine monophosphate
- cGMP cyclic guanosine monophosphate
- the intracellular concentration of cGMP is increased by stimulating the soluble or membrane-bound guanylate cyclases.
- the intracellular The concentration of cAMP can be modulated by activating so-called G protein-coupled receptors, which activate G proteins and thus activate or inhibit the adenylate cyclase.
- the phosphodiesterases are divided into eleven different classes according to their biochemical or pharmacological properties (Soderling and
- Phosphodiesterase 9A is a cGMP-specific phosphodiesterase.
- the enzyme has a Km (Michaelis-Menten constant) of 70 nM (Soderling et. Al., J. Biol. Chem. (1998) 15553-15558), this is the lowest known Km for cGMP of all known phosphodiesterases , Therefore, the PDE9A is involved in the maintenance or regulation of the basal, intracellular cGMP level.
- the DNA and protein sequences for phosphodiesterase 9A are from the mouse
- the present invention therefore relates to the use of phosphodiesterase 9A inhibitors for the production of a medicament for the treatment and / or prophylaxis of the abovementioned diseases.
- inhibitors are all substances which prevent (inhibit) activation or the biological activity of the enzyme.
- the inhibition can be measured, for example, in the cGMP assay described below.
- Particularly preferred inhibitors are low molecular weight substances.
- inhibition means an at least 10% decrease in activity or an at least 10% increase in intracellular cGMP concentration in a cell which contains phosphodiesterase 9A.
- Inhibitors can be tested on PDE9A purified or recombinantly expressed and purified from suitable tissue.
- These cells are preferably cells from the smooth musculature of vessels or from cell lines which express the PDE9A recombinantly.
- Preferred PDE9A inhibitors are those which inhibit in the activity test given below with an IC 50 of 1 ⁇ M, preferably less than 0.1 ⁇ M.
- PDE9A inhibitors The effect of PDE9A inhibitors is tested on the isolated enzyme.
- the phosphodiesterase [3H] cGMP SPA enzyme assay kit from Amersham can be used. The test is carried out according to the manufacturer's instructions.
- a suitable dilution of the enzyme various concentrations of the inhibitor (dilution series typically of 10 “9 -10 “ 5 M) and [3H] cGMP (0.05 ⁇ Ci per batch) are used on a 96-well microtiter plate ) incubated for 15 min at 30 ° C. After the reaction has stopped, the “SPA beads” are added and the microtiter plate is shaken for 30 seconds. After 60 minutes, the measurement is carried out using a scintillation measuring device suitable for microtiter plates (eg 1450 MicroBeta, Wallac).
- a scintillation measuring device suitable for microtiter plates (eg 1450 MicroBeta, Wallac).
- the ICs ö value of the action of a PDE9A inhibitor is the value at which 50% of the cGMP degradation is inhibited by the PDE9A. Quantification of mRNA expression of PDE9A and PDE5A in human tissues
- the relative expression of PDE9A in human tissues is determined by quantifying the mRNA using the real-time polymerase chain reaction (PCR)
- PCR For the PCR, 7.5 ⁇ l of primer / probe mix and 12.5 ⁇ l of TaqMan Universal Master Mix (from Applied Biosytems) are added to 5 ⁇ l of the diluted cDNA solution. The final concentration of each primer is 300 nM, that of the probe 150 nM.
- the sequence of the "forward" and “reverse” primer for PDE9A is: 5 C - TCCCGGCTACAACAACACGT-3 'or 5'-AGATGTCATTGTAGCGGACCG-3', the • sequence of the fluorescence-labeled probe 5'-6FAM-
- the position of the amplicon is chosen so that all four described splice variants of the PDE9A mRNA (PDE9A 1- ) are detected.
- PDE9A 1- the sequence of the "forward" is
- the PCR is carried out on an ABI Prism SDS 7700 device (from Applied Biosystems) according to the manufacturer's instructions. 40 cycles are carried out as standard. For each tissue, a so-called “threshold cycle” (Ct value) is obtained. The Ct value corresponds to the cycle in which the fluorescence intensity of the released probe reaches 10 times the background signal. The lower the Ct value The amplification therefore begins earlier, ie the more mRNA is contained in the original sample. To compensate for any fluctuations in cDNA synthesis, the expression of a so-called “housekeeping gene” is also analyzed in all examined tissues. This should be expressed approximately equally strongly in all tissues.
- ⁇ -actin is used for this.
- the sequence of the "forward” or “reverse” primer for human cytosolic ß-actin is 5'-TCCACCTTCCAGCAGATGTG-3 ', and 5'-CTAGAAGCATTTGCGGTGGAC-3' the sequence of the probe 5'-6FAM-ATCAGCAAGCAGGCAGCCATGACGAGAG '.
- anesthetized rats are quickly removed from the heart and inserted into a conventional Langendorff apparatus.
- the coronary arteries are perfused at a constant volume (10 ml / min) and the resulting perfusion pressure is registered using a suitable pressure transducer.
- a decrease in the perfusion pressure in this arrangement corresponds to a relaxation of the coronary arteries.
- the pressure (LVP) which is developed by the heart during each contraction, is measured via a balloon inserted into the left ventricle and another pressure transducer.
- the frequency of the isolated beating heart is calculated from the number of contractions per unit of time.
- the test substances are added in an increasing concentration series (usually 10-9 M to 10-6 M) with the help of a perfuser.
- the PDE9A inhibitors can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
- the therapeutically active compound should in each case be present in a concentration of 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
- the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, for example in the case of.
- solvents and / or carriers optionally using emulsifiers and / or dispersants, for example in the case of.
- Use of water as a diluent, optionally organic solvents as auxiliary. solvents can be used.
- the application is carried out in the usual way, preferably orally, transdermally, intravenously or parenterally, in particular orally or intravenously. However, it can also be done by inhalation via the mouth or nose, for example with the aid of a spray, or topically via the skin.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10156249 | 2001-11-15 | ||
| DE10156249A DE10156249A1 (de) | 2001-11-15 | 2001-11-15 | Regulation der cGMP-spezifischen Phosphodiesterase 9A |
| PCT/EP2002/012550 WO2003041725A2 (de) | 2001-11-15 | 2002-11-11 | REGULATION DER cGMP-SPEZIFISCHEN PHOSPHODIESTERASE 9A |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1448210A2 true EP1448210A2 (de) | 2004-08-25 |
Family
ID=7705937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02772410A Withdrawn EP1448210A2 (de) | 2001-11-15 | 2002-11-11 | REGULATION DER cGMP-SPEZIFISCHEN PHOSPHODIESTERASE 9A |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20040266736A1 (https=) |
| EP (1) | EP1448210A2 (https=) |
| JP (1) | JP2005511619A (https=) |
| AU (1) | AU2002337186A1 (https=) |
| DE (1) | DE10156249A1 (https=) |
| WO (1) | WO2003041725A2 (https=) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10238722A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Selektive Phosphodiesterase 9A-Inhibitoren als Arzneimittel zur Verbesserung kognitiver Prozesse |
| DE10238723A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
| DE10238724A1 (de) | 2002-08-23 | 2004-03-04 | Bayer Ag | Alkyl-substituierte Pyrazolpyrimidine |
| DE10320785A1 (de) | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Arylmethyl-substituierte Pyrazolopyrimidine |
| US8044060B2 (en) | 2003-05-09 | 2011-10-25 | Boehringer Ingelheim International Gmbh | 6-cyclylmethyl- and 6-alkylmethyl pyrazolo[3,4-D]pyrimidines, methods for their preparation and methods for their use to treat impairments of perception, concentration learning and/or memory |
| DE10328479A1 (de) | 2003-06-25 | 2005-01-13 | Bayer Ag | 6-Arylamino-5-cyano-4-pyrimidinone |
| DE102004001873A1 (de) | 2004-01-14 | 2005-09-29 | Bayer Healthcare Ag | Cyanopyrimidinone |
| WO2006061994A1 (ja) * | 2004-12-08 | 2006-06-15 | Takeshi Yamamoto | 遺伝子配列検査法 |
| DE102005024494A1 (de) * | 2005-05-27 | 2006-11-30 | Bayer Healthcare Ag | Verwendung von Cyanopyrimidinen |
| JP5498392B2 (ja) | 2007-11-30 | 2014-05-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | １，５−ジヒドロ−ピラゾロ［３，４−ｄ］ピリミジン−４−オン誘導体及びｃｎｓ障害の治療のためのｐｄｅ９ａモジュレーターとしてのそれらの使用 |
| UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
| JP5453431B2 (ja) | 2008-09-08 | 2014-03-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピラゾロピリミジン及びｃｎｓ障害の治療のためのそれらの使用 |
| PE20120505A1 (es) | 2009-03-31 | 2012-05-09 | Boehringer Ingelheim Int | Derivados de 1-heterociclil-1,5-dihidro-pirazolo[3,4-d]pirimidin-4-ona como moduladores de pde9a |
| AR077859A1 (es) * | 2009-08-12 | 2011-09-28 | Boehringer Ingelheim Int | Compuestos para el tratamiento de trastornos del snc |
| AP2012006631A0 (en) | 2010-08-12 | 2012-12-31 | Boehringer Ingelheim Int | 6-Cycloalkyl-1, 5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivatives and their use as PDE9A inhibitors |
| US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
| SG11202109781QA (en) * | 2019-03-08 | 2021-10-28 | Transthera Sciences Nanjing Inc | Uses of phosphodiesterase inhibitors |
| CN120329388B (zh) * | 2025-04-30 | 2025-09-26 | 中日友好医院(中日友好临床医学研究所) | 一种双靶点多肽及其在心衰治疗中的应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4211239C2 (de) * | 1992-04-03 | 1995-11-16 | Max Planck Gesellschaft | Arzneimittel gegen Herz-Kreislauf-Erkrankungen |
| US5922595A (en) * | 1997-12-09 | 1999-07-13 | Incyte Pharmaceuticals, Inc. | Cyclic GMP phosphodiesterase |
-
2001
- 2001-11-15 DE DE10156249A patent/DE10156249A1/de not_active Withdrawn
-
2002
- 2002-11-11 WO PCT/EP2002/012550 patent/WO2003041725A2/de not_active Ceased
- 2002-11-11 US US10/495,638 patent/US20040266736A1/en not_active Abandoned
- 2002-11-11 AU AU2002337186A patent/AU2002337186A1/en not_active Abandoned
- 2002-11-11 JP JP2003543612A patent/JP2005511619A/ja not_active Withdrawn
- 2002-11-11 EP EP02772410A patent/EP1448210A2/de not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03041725A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE10156249A1 (de) | 2003-05-28 |
| WO2003041725A3 (de) | 2004-03-18 |
| WO2003041725A2 (de) | 2003-05-22 |
| US20040266736A1 (en) | 2004-12-30 |
| JP2005511619A (ja) | 2005-04-28 |
| AU2002337186A1 (en) | 2003-05-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1448210A2 (de) | REGULATION DER cGMP-SPEZIFISCHEN PHOSPHODIESTERASE 9A | |
| EP1534285B1 (de) | Selektive phosphodiesterase 9a-inhibitoren als arzneimittel zur verbesserung kognitiver prozesse | |
| Foster et al. | Interaction of age and chronic estradiol replacement on memory and markers of brain aging | |
| EP1534711B1 (de) | Phenyl-substituierte pyrazolopyrimidine | |
| Coull | Pharmacological manipulations of the α2-noradrenergic system: effects on cognition | |
| EP1534713B1 (de) | Alkyl-substituierte pyrazolopyrimidine | |
| Sato et al. | Effects of cholinergic depletion on neuron activities in the cat visual cortex | |
| DE69937198T2 (de) | Behandlung der alzheimer-krankheit durch erhöhung des cytidin-spiegels in vivo | |
| DE60116352T2 (de) | Verwendung von kcnq kaliumkanalagonisten zur herstellung eines arzneimittels zur modulierung der blasenfunktion | |
| EP0590551B1 (de) | Neue therapeutische Verwendungen von Phthalazinon-Derivaten | |
| DE69725721T2 (de) | Vorbeugende oder heilende mittel für krankheiten, die durch mangel an stickoxid-synthase (nos) ausgelöst sind | |
| Nattie et al. | Ventral medulla sites of muscarinic receptor subtypes involved in cardiorespiratory control | |
| Classen et al. | Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs | |
| EP1416952A1 (de) | Regulation des apj-rezeptors zur behandlung oder prophylaxe von herzkrankheiten | |
| EP1644339B1 (de) | 6-arylamino-5-cyano-4-pyrimidinone als pde9a-inhibitoren | |
| EP2124955A2 (de) | Inhibition der pde2a | |
| DE60125171T2 (de) | Verfahren zur detektion und quantifizierung von menschlichen p450-molekülen und sonde und kit für dieses verfahren | |
| DE4211239C2 (de) | Arzneimittel gegen Herz-Kreislauf-Erkrankungen | |
| DE60226313T2 (de) | Verwendung von sesquiterpene enthaltenden zusammenstellungen zur behandlung von krebs | |
| DE60029110T2 (de) | Verfahren zur identifizierung neuartiger gene, die bei der regulation der angiogenese einer rolle spielen, analyse dieser gene sowie ihre verwendung zu therapeutischen zwecken | |
| DE10332685A1 (de) | Vorhof-selektiv exprimierte Kaliumkanäle | |
| DE69430047T2 (de) | Pharmazeutische Zusammensetzungen die Isochinolinderivate enthalten | |
| Pepeu et al. | The central cholinergic system during aging | |
| DE102005042877A1 (de) | Inhibition der PDE1A | |
| Rinkel | Pharmacodynamics of LSD and mescaline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR |
|
| AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO SI |
|
| 17P | Request for examination filed |
Effective date: 20040920 |
|
| 17Q | First examination report despatched |
Effective date: 20060807 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20061218 |