US20020006926A1 - Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of parkinson's disease - Google Patents
Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of parkinson's disease Download PDFInfo
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- ONYNFPDFOCCGSX-UHFFFAOYSA-N C.C1=CC=C2OC=CC2=C1.C1=CC=C2OCCC2=C1 Chemical compound C.C1=CC=C2OC=CC2=C1.C1=CC=C2OCCC2=C1 ONYNFPDFOCCGSX-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N C1=CC=CC=C1 Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- CHHKDQSCLAHJFJ-BDRKCOQDSA-N CC.CC.CC.CC.CC.[H]N1C2=C(C=CC=C2)C2=C1C(C1=CC=CC=C1)N(C(=O)/C=C/C)CC2 Chemical compound CC.CC.CC.CC.CC.[H]N1C2=C(C=CC=C2)C2=C1C(C1=CC=CC=C1)N(C(=O)/C=C/C)CC2 CHHKDQSCLAHJFJ-BDRKCOQDSA-N 0.000 description 1
- JLUKEFOPDKXPCA-UHFFFAOYSA-N CC.CC1C(=O)N2C(C)C3=C(CC2C(=O)N1C)C1=C(C=CC=C1)N3.II Chemical compound CC.CC1C(=O)N2C(C)C3=C(CC2C(=O)N1C)C1=C(C=CC=C1)N3.II JLUKEFOPDKXPCA-UHFFFAOYSA-N 0.000 description 1
- SEKMOBMPCNLLLI-UHFFFAOYSA-N COC1=C(C2=NC3=C(C(=O)N2)N(C)N=C3C)C=C(C)C=C1 Chemical compound COC1=C(C2=NC3=C(C(=O)N2)N(C)N=C3C)C=C(C)C=C1 SEKMOBMPCNLLLI-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
Definitions
- the present invention relates generally to novel therapeutic methods for treating Parkinson's Disease by administering cyclic GMP-specific phosphodiesterase inhibitor compounds.
- Parkinson's Disease is a progressive degenerative disorder of the central nervous system (CNS) characterized by tremor and impaired muscular coordination. It is fatal if untreated. PD has been reported to affect approximately one percent of Americans over fifty years of age, but unrecognized early symptoms of the disease may be present in as many as ten percent of those over 60 years of age. The current prediction is that one to one and one-half million persons in the United States may be suffering from PD. The disease may appear at any age, but the risk of developing it increases with age. The occurrence of PD is therefore expected to increase in the next one-half century as the average age of individuals in developed countries progressively increases. For the United States, this phenomenon of population aging is predicted to result in a threefold to fourfold increase in PD frequency or several million persons afflicted with PD.
- PD Like some other CNS degenerative disorders, PD begins insidiously. Persons close to the patient may notice the problem before the patient does. The patient's facial expression may appear depressed or apathetic (masked faces) and their voice may become softer in volume and monotonous in tone. The patient may complain of muscular weakness or stiffness. Involuntary movements, such as tremor or the turning in of a foot (dystonia) may become a problem. These symptoms may be noticed during routine activities or they may be present only at certain times such as when the patient is walking or writing. In the initial stages of PD, many patients do not have movement problems. Instead, they may complain of anxiety and difficulty sleeping. However, signs of motor system dysfunction become apparent upon neurologic and physical examination.
- the hallmark physical signs of PD are tremor, cogwheel rigidity and bradykinesia. Poor postural reflexes are sometimes included as the fourth hallmark sign. When postural reflexes are inadequate, patients may fall if they are pushed even slightly forward or backward, or if they are standing in a moving vehicle such as a bus or train. In PD, tremor typically occurs at rest but may also be present when the arms are raised (postural tremor).
- Cogwheel rigidity refers to increased tone that is felt by the examiner as a ratchet-like resistance during passive range of motion. Bradykinesia means slowed nonvolitional and/or volitional movements. The masked faces of PD are an example of slowed nonvolitional movement.
- the mean duration of PD is about fourteen years. However, without treatment, the period between presentation of clinical features and death is reduced to about nine years. The rate of disease progression is believed to be directly correlated to the rate of neuron loss.
- Symptomatic therapies are the most common form of treatment for PD. These remedies attempt to fulfill the basic dictate of traditional medicine, to relieve suffering. These drugs are designed to be used as either monotherapy or adjunctive symptomatic therapy but have little, if any, beneficial effects on underlying disease cause or pathogenesis.
- the symptomatic compounds can be divided into two groups on the basis of their pharmacologic action—dopaminergic drugs and nondopaminergic drugs.
- L-dopa is dopamine precursor therapy. L-dopa crosses the blood-brain barrier penetrating into the brain, where it is converted to dopamine via the enzyme dopa decarboxylase. L-dopa has poor bioavailability and a short half-life when administered as monotherapy.
- L-dopa is formulated with a decarboxylase inhibitor.
- the decarboxylase inhibitor carbidopa is contained in virtually all L-dopa products prescribed during the last 20 years.
- L-dopa has served as the mainstay of PD therapy.
- long term treatment with L-dopa often results in disabling complications.
- Many patients develop unsustained or unpredictable responses to L-dopa along with drug-induced involuntary movements. It has even been postulated by Mena, et al., Mov Disord 7:23 (1992), that L-dopa may be neurotoxic and thereby accelerates nigral neuronal degeneration.
- dopamine agonists have been developed for use as monotherapy in early PD to postpone the need to initiate L-dopa therapy and for use as adjunctive therapy later in the disease to permit reduction of L-dopa dosing or enhancement of beneficial dopaminergic effects.
- Agonists directly stimulate dopamine receptors within the brain, and thus their action is independent of L-dopa.
- Blockade of other metabolic enzymatic pathways can also be used to enhance the effects of L-dopa or to maintain brain dopamine levels.
- One of the central metabolic pathways for dopamine is mediated via the enzyme monoamine oxidase type B (MAOB).
- MAOB monoamine oxidase type B
- Another MAOB inhibitor, lazabemide was initially tested as adjunctive therapy in PD, but it is not being actively developed at this time. Hubble, J P, Med Clinics of North America 83(2):525-536 (1999).
- the compound rasagiline also inhibits the oxidative monoamine metabolic enzymes. Rasagiline's effects in early untreated PD are being investigated. Hubble, supra.
- Cyclic nucleotide phosphodiesterases are essential regulators of cyclic nucleotide-dependent signal transduction processes. They terminate the action of the second messengers adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) by hydrolyzing them to their respective 5′-nucleoside monophosphates. Based on their biological properties, the PDEs may be classified into several general families.
- Ca +2 /calmodulin-stimulated PDE (Type I), cGMP-stimulated PDE (Type II), cGMP-inhibited PDE (Type III), cAMP-specific PDE (Type IV), cGMP-specific PDE (Type V), and cGMP-specific photoreceptor PDE (Type VI).
- caffeine is known to non-selectively inhibit the action of a cyclic 3′,5′-nucleotide phosphodiesterase known to hydrolyze cAMP.
- a cyclic 3′,5′-nucleotide phosphodiesterase known to hydrolyze cAMP.
- concomitant administration of caffeine and bromocriptine to patients with PD failed to potentiate the anti-parkinson action of bromocriptine.
- Shoulson, et al., Neurology 25:722-724 (1975) demonstrated similar results when caffeine was administered in combination with levodopa or piribedil.
- U.S. Pat. No. 4,147,789 discloses the combination of 6-methyl-8-thiomethyl-ergolene derivatives with nonselective phosphodiesterase inhibitors for treatment of PD.
- U.S. Pat. No. 4,147,789 does not disclose using specific phosphodiesterase inhibitors nor does it disclose combining L-dopa with phosphodiesterase inhibitors.
- the present invention provides novel therapeutic uses for Type V PDE inhibitors in patients suffering from PD.
- the invention provides methods of preventing and/or slowing the progression of PD or reducing or eliminating clinical symptoms of PD by administering a therapeutically effective amount of one or more Type V PDE (PDE5) inhibitor(s) of the invention.
- PDE5 Type V PDE
- a “clinical symptom” of PD includes tremor, cogwheel rigidity, bradykinesia, poor postural reflexes, and any other clinically defined physical or mental manifestation of PD.
- IC 50 is defined as the concentration of a compound that results in 50% enzyme inhibition, in a single dose response experiment.
- the IC 50 value therefore is a measure of the potency of a compound to inhibit PDEs, including PDE5. Determining the IC 50 value of a compound is readily carried out by a known in vitro methodology generally described in Cheng et al., Biochem Pharmacology 22:3099-3108 (1973).
- inhibiting refers to blocking the enzymatic activity of PDE5 to a sufficient degree to reduce a clinical symptom of PD or to prevent the recurrence of a clinical symptom of PD.
- a pharmaceutically effective amount represents an amount of a compound that is capable of inhibiting PDE5, and causes an improvement in a clinical symptom of PD and/or prevents or reduces recurrence of the symptom.
- PDE5 inhibitor refers to a compound that inhibits PDE5.
- a PDE5 inhibitor useful in the present invention is a compound that inhibits PDE5 and has an IC 50 value against human recombinant PDE5 of about 10 nM or less.
- the IC 50 value of the PDE5 inhibitor is about 5 nM or less, more preferably about 3 nM or less, and most preferably about 1 nM or less.
- Most preferred PDE5 inhibitors are selective PDE5 inhibitors, i.e., those that inhibit PDE5, but do not significantly inhibit other PDE enzymes, particularly PDE6 and PDE1c.
- a preferred PDE5 inhibitor exhibits a PDE6/PDE5 and a PDE1c/PDE5 IC 50 inhibition quotient of at least 200, and can range to 1,000 or greater.
- the PDE6/PDE5 IC 50 inhibition quotient is the ratio of the IC 50 value of a compound vs PDE6 to the IC 50 value of the same compound vs PDE5.
- the PDE1c/PDE5 inhibition quotient is identically defined for PDE1c and PDE5.
- the compound has a PDE6/PDE5 and a PDE1c/PDE5 IC 50 inhibition quotient of at least 100 and an IC 50 for PDE5 of about 5 nM or less, e.g., about 0.1 to about 5 nM. Therefore, for preferred inhibitors, the IC 50 value of the PDE5 inhibitor is about 100 times less than the IC 50 value against PDE6 or PDEIc, more preferably about 500 times less than the IC 50 value against PDE6 or PDEIc, and most preferably about 1000 times less than the IC 50 value against PDE6 or PDEIc.
- PDE5 inhibitors useful in the present invention vary significantly in chemical structure and the use of a PDE5 inhibitor in the present method is not dependent on a particular chemical structure.
- preferred compounds having the ability to inhibit PDE5 include compounds having the structural formula (I):
- R 1 is methyl or ethyl
- R 2 is n-propyl
- R 3 is ethyl, n-propyl, or allyl
- R 4 is COCH 2 NR 5 R 6 , CONR 5 R 6 , SO 2 NR 9 R 10 , or 1-methyl-2-imidazolyl
- R 5 and R 6 together represent, with the nitrogen atom to which they are attached, a morpholino or 4-N(R 11 )-piperazinyl group
- R 9 and R 10 together with the nitrogen atom to which they are attached represent a 4-N(R 2 )-piperazinyl group
- R 11 is methyl or acetyl
- R 12 is H, methyl, 2-propyl, or 2-hydroxyethyl.
- R 13 is selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl
- R 14 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-3 alkyl, and arylC 1-3 alkyl, wherein aryl is phenyl or phenyl substituted with one to three substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and methylenedioxy, and heteroarylC 1-3 alkyl, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 alkoxy.
- R 15 represents an optionally substituted monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring
- the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen;
- R 16 represents hydrogen or C 1-3 alkyl, or R 14 and R 16 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring.
- Preferred compounds of structural formula (II) are those wherein R 13 is hydrogen, halogen, or C 1-6 alkyl; R 14 is hydrogen or C 1-6 alkyl; R 15 is the bicyclic ring
- Preferred compounds of structural formula (II) include:
- Still other exemplary PDE5 inhibitors useful in the present method are those disclosed in Daugan et al. U.S. Pat. No. 6,001,847; WO 97/43287, WO 98/53819, WO 99/21831, WO 99/24433, WO 99/26946, WO 99/28319, WO 99/28325, WO 99/42452, WO 99/54284, WO 99/54333, each incorporated herein by reference.
- ring C represents a 5- or 6-membered heteroaryl group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
- R 17 represents hydrogen or halogen
- R 18 is selected from the group consisting of hydrogen, nitro (NO 2 ), trifluoromethyl, trifluoromethoxy, halogen, cyano (CN),
- R 19 is selected from the group consisting of hydrogen, halogen, OR h , C 1-6 alkyl, NO 2 , and NR h R′;
- R 18 and R 19 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
- R 20 is selected from the group consisting of hydrogen, halogen, NO 2 , trifluoromethoxy, C 1-6 alkyl, OC 1-6 alkyl, and C( ⁇ O)O h ;
- R 21 is hydrogen
- R 20 and R 21 are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
- Het represents a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and is optionally substituted with C 1-4 alkyl;
- R h and R′ can be the same or different, and are independently selected from hydrogen and C 1-6 alkyl;
- R j represents phenyl or C 4-6 cycloalkyl, wherein the phenyl or C 4-6 cycloalkyl can be optionally substituted with one or more halogen atoms, one or more C( ⁇ O)OR a , or one or more OR h ;
- n is an integer 1, 2, or 3;
- m is an integer 1 or 2.
- C is a heteroaryl group containing at least one nitrogen or sulfur
- R 19 is hydrogen
- R 18 is selected from the group consisting of NR h R i and a 5- or 6-membered heterocyclic group containing at least one nitrogen optionally substituted with C 1-4 alkyl.
- the PDE5 inhibitors may be concurrently administered with other drugs, including other known anti-PD drugs, in which case the dosage of each agent required to exert a therapeutic effect during combinative therapy may be less than the dosage necessary for monotherapeutic effectiveness.
- drugs for concurrent administration include, but are not limited to, L-dopa, carbo-levo, apomorphine, pirebedil, bromocriptine, carbergoline, pramipexole, ropinirole, selegiline, lazabemide, rasagiline, sildenafil citrate (Viagra), caffeine, Mirapex, Naprelan, Oxybutin and aspirin.
- the invention further provides uses of PDE5 inhibitors in the manufacture of a medicament for treating PD.
- Assays to determine the specific activity of PDE5s are well known in the art and any such assay can be used to identify inhibitors useful in the therapeutic methods disclosed herein.
- Preferred inhibitors possess desirable physical and biological properties, e.g., a sufficient water solubility, bioavailability, and metabolic stability, for therapeutic use in the treatment of PD.
- Anti-PD therapeutically effective amounts of PDE5 inhibitors include amounts effective for slowing or preventing the progression of PD and amounts effective to alleviate or reduce the clinical symptoms of PD.
- PDE5 inhibitors can be administered to humans at doses ranging from about 0.1 mg to about 1000 mg daily or more preferably at doses ranging from about 1 mg to about 100 mg daily for adults. Even more preferably, doses range from about 2 mg to about 20 mg over a 24 hour period. Most preferable are doses calculated to provide an effective circulating blood level. Equivalent dosing of PDE5 inhibitors can be administered at longer intervals, e.g., larger doses once or twice weekly.
- the dosage of the drug may be increased or decreased, and the duration of treatment may be shortened or lengthened as determined by the treating physician.
- the frequency of dosing will depend on the pharmacokinetic parameters of the agents and the route of administration.
- the optimal pharmaceutical formulation will be determined by one skilled in the art depending upon the route of administration and desired dosage. See for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712, the disclosure of which is hereby incorporated by reference. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of administered agents.
- the final dosage regimen will be determined by the attending physician, considering various factors which modify the action of drugs, e.g., the drug's specific activity, the severity of the damage and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of the clinical symptoms, time of administration and other clinical factors.
- PDE5 inhibitors may be administered systemically via, e.g., oral, intravenous, intramuscular or subcutaneous routes.
- the drug may be aerosolized for pulmonary administration, formulated in a spray for nasal administration, administered intraventricularly or intrathecally into the cerebrospinal fluid, or administered intravenously via continuous infusion pump.
- the drugs may also be administered topically via, e.g., drops (particularly ophthalmic drops), ointment, patch or per rectum via e.g., suppositories or enemas.
- PDE5 inhibitors and another anti-PD agent can be administered simultaneously or sequentially.
- compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
- These compositions can be administered by a variety of routes including oral, buccal, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
- Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
- Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
- the active ingredient usually is mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- a carrier which can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
- compositions used in the invention can be formulated to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- compositions preferably are formulated in a unit dosage form.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the active compounds generally are effective over a wide dosage range. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances.
- Example 1 describes the preparation of PDE5.
- Example 2 describes an assay for PDE5 activity.
- Example 3 describes assays to measure the effects of PDE5 inhibitors.
- Example 4 describes administration of a PDE5 inhibitor compound to a patient suffering from PD.
- yeast transformation vector employed which is derived from the basic ADH2 plasmid described in V. Price et al., Methods in Enzymology, 185, pages 308-318 (1990) incorporated yeast ADH2 promoter and terminator sequences rather than ADH1 promoter and terminator sequences and the Saccharomyces cerevisiae host was the protease-deficient strain BJ2-54 deposited on Aug. 31, 1998 with the American Type Culture Collection, Manassas, Va., under accession number ATCC 74465.
- Transformed host cells were grown in 2X SC-leu medium, pH 6.2, with trace metals, and vitamins. After 24 hours, YEP medium containing glycerol was added to a final concentration of 2X YEP/3% glycerol. Approximately 24 hours later, cells were harvested, washed, and stored at ⁇ 70° C.
- Cell pellets (29 g) were thawed on ice with an equal volume of lysis buffer (25 mM Tris-CI, pH 8, 5 mM MgCl 2 , 0.25 mM dithiothreitol, 1 mM benzamidine, and 10 ⁇ M ZnSO 4 ).
- lysis buffer 25 mM Tris-CI, pH 8, 5 mM MgCl 2 , 0.25 mM dithiothreitol, 1 mM benzamidine, and 10 ⁇ M ZnSO 4 .
- Cells were lysed in a microfluidizer with N 2 at 20,000 psi. The lysate was centrifuged and filtered through 0.45 ⁇ M disposable filters. The filtrate was applied to a 150 ml column of Q Sepharose Fast Flow (Pharmacia).
- the column was washed with 1.5 volumes of Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCl 2 , 0.25 mM dithiothreitol, 10 ⁇ M ZnSO 4 ) and eluted with a step gradient of 125 mM NaCl in Buffer A followed by a linear gradient of 125-1000 mM NaCI in Buffer A.
- Buffer A 20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCl 2 , 0.25 mM dithiothreitol, 10 ⁇ M ZnSO 4
- Active fractions were pooled, precipitated with 60% ammonium sulfate, and resuspended in Buffer C (20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM dithiothreitol, and 10 ⁇ M ZnSO 4 ).
- Buffer C 20 mM Bis-Tris Propane, pH 6.8, 125 mM NaCl, 0.5 mM dithiothreitol, and 10 ⁇ M ZnSO 4 .
- the pool was applied to a 140 ml column of Sephacryl S-300 HR and eluted with Buffer C. Active fractions were diluted to 50% glycerol and stored at ⁇ 20° C. The resultant preparations were about 85% pure by SDS-PAGE.
- Activity of PDE5 preparations can be measured by standard assays in the art. For example, specific activity of any PDE can be determined as follows. PDE assays utilizing a charcoal separation technique are performed essentially as described in Loughney, et al., J. Biol. Chem. 271:796-806 (1996). In this assay, PDE5 activity converts [ 32 P]cGMP to [ 32 P]5′GMP in proportion to the amount of PDE5 activity present. The [ 32 P]5′GMP is then quantitatively converted to free [ 32 P] phosphate and unlabeled adenosine by the action of snake venom 5′-nucleotidase.
- the amount of [ 32 P] phosphate liberated is proportional to enzyme activity.
- the assay is performed at 30° C in a 100 ⁇ L reaction mixture containing (final concentrations) 40 mM Tris-Cl (pH 8.0), 1 ⁇ M ZnSO 4 , 5 mM MgCl 2 , and 0.1 mg/ml bovine serum albumin.
- PDE5 is present in quantities that yield ⁇ 30% total hydrolysis of substrate (linear assay conditions).
- the assay is initiated by addition of substrate (1 mM [ 32 P]cGMP), and the mixture is incubated for twelve minutes.
- the first of the assays is performed in a total volume of 200 ⁇ l containing 50 mM Tris pH 7.5, 3 mM Mg acetate, 1 mM EGTA, 50 ⁇ g/ml snake venom nucleotidase and 50 nM [ 3 H]-cGMP (Amersham).
- Compounds of the invention are dissolved in DMSO finally present at 2% in the assay.
- the assays are incubated for 30 minutes at 30° C. and stopped by addition of 800 ⁇ l of 10 mM Tris pH 7.5, 10 mM EDTA, 10 mM theophylline, 0.1 mM adenosine, and 0.1 mM guanosine.
- the mixtures are loaded on 0.5 ml QAE Sephadex columns, and eluted by 2 ml of 0.1M formate (pH 7.4). The eluted radioactivity is measured by scintillation counting in Optiphase Hisafe
- a second, microplate PDE assay uses Multiscreen plates and a vacuum manifold.
- the assay (100 ⁇ l) contains 50 mM Tris pH 7.5, 5 mM Mg acetate, 1 mM EGTA and 250 pg/ml snake venom nucleotidase.
- the other components of the reaction mixture are as described above.
- the total volume of the assay is loaded on a QAE Sephadex microcolumn plate by filtration. Free radioactivity is eluted with 200 ⁇ l of water from which 50 ⁇ l aliquots are analyzed by scintillation counting as described above.
- a patient who was administered a PDE5 inhibitor of the invention noted an improvement in his Parkinson's symptoms, i.e., a reduction in his symptoms.
- the PDE5 inhibitor was 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, otherwise known as sildenafil citrate (Viagra®).
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/836,744 US20020006926A1 (en) | 2000-04-19 | 2001-04-17 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of parkinson's disease |
US09/989,672 US6492371B2 (en) | 2000-04-19 | 2001-11-21 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of Parkinson's Disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19818000P | 2000-04-19 | 2000-04-19 | |
US09/836,744 US20020006926A1 (en) | 2000-04-19 | 2001-04-17 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of parkinson's disease |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US09/989,672 Continuation US6492371B2 (en) | 2000-04-19 | 2001-11-21 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of Parkinson's Disease |
Publications (1)
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US20020006926A1 true US20020006926A1 (en) | 2002-01-17 |
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ID=22732318
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/836,744 Abandoned US20020006926A1 (en) | 2000-04-19 | 2001-04-17 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of parkinson's disease |
US09/989,672 Expired - Fee Related US6492371B2 (en) | 2000-04-19 | 2001-11-21 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of Parkinson's Disease |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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US09/989,672 Expired - Fee Related US6492371B2 (en) | 2000-04-19 | 2001-11-21 | Use of cyclic GMP-specific phosphodiesterase inhibitors for treatment of Parkinson's Disease |
Country Status (9)
Country | Link |
---|---|
US (2) | US20020006926A1 (de) |
EP (1) | EP1278522B1 (de) |
JP (1) | JP2004500425A (de) |
CN (1) | CN1436080A (de) |
AT (1) | ATE343388T1 (de) |
AU (2) | AU2001255849B8 (de) |
CA (1) | CA2407031A1 (de) |
DE (1) | DE60124085D1 (de) |
WO (1) | WO2001078711A2 (de) |
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TW200815045A (en) * | 2006-06-29 | 2008-04-01 | Jazz Pharmaceuticals Inc | Pharmaceutical compositions of ropinirole and methods of use thereof |
US8841300B2 (en) | 2006-10-02 | 2014-09-23 | Jerry M. Held | Treatment for Parkinson's disease—combination high dose serotonergic synaptic reuptake inhibitor with phosphodiesterase inhibitor |
ES2411604T3 (es) * | 2006-11-13 | 2013-07-05 | Intra-Cellular Therapies, Inc. | Compuestos orgánicos |
JP5837278B2 (ja) | 2006-12-05 | 2015-12-24 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | 新規使用 |
JP2010527928A (ja) * | 2007-05-18 | 2010-08-19 | ヴィヴァス・インコーポレイテッド | ホスホジエステラーゼ−5阻害剤を含む新規の組み合わせおよびそれらの使用 |
CN101969774A (zh) * | 2007-12-06 | 2011-02-09 | 细胞内治疗公司 | 有机化合物 |
EP2939676A1 (de) * | 2007-12-06 | 2015-11-04 | Intra-Cellular Therapies, Inc. | Organische Verbindungen |
WO2009147681A1 (en) | 2008-06-06 | 2009-12-10 | Pharma Two B Ltd. | Pharmaceutical compositions for treatment of parkinson's disease |
EA201170772A1 (ru) | 2008-12-06 | 2012-03-30 | Интра-Селлулар Терапиз, Инк. | Органические соединения |
EP2358204B1 (de) * | 2008-12-06 | 2015-08-05 | Intra-Cellular Therapies, Inc. | 4,5,7,8-Tetrahydro-4-oxo-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidin- Verbindungen als PDE1 Inhibitoren. |
CN102223799A (zh) | 2008-12-06 | 2011-10-19 | 细胞内治疗公司 | 有机化合物 |
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MX2011005935A (es) | 2008-12-06 | 2011-12-16 | Intra Cellular Therapies Inc | Compuestos organicos. |
WO2010098839A1 (en) | 2009-02-25 | 2010-09-02 | Intra-Cellular Therapies, Inc. | Pde 1 inhibitors for ophthalmic disorders |
US9468637B2 (en) | 2009-05-13 | 2016-10-18 | Intra-Cellular Therapies, Inc. | Organic compounds |
WO2011016861A2 (en) | 2009-08-05 | 2011-02-10 | Intra-Cellular Therapies, Inc. | Novel regulatory proteins and inhibitors |
WO2011153138A1 (en) | 2010-05-31 | 2011-12-08 | Intra-Cellular Therapies, Inc. | Organic compounds |
EP2575817A4 (de) | 2010-05-31 | 2014-01-08 | Intra Cellular Therapies Inc | Organische verbindungen |
JP5894148B2 (ja) | 2010-05-31 | 2016-03-23 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | 有機化合物 |
TW201206937A (en) | 2010-05-31 | 2012-02-16 | Intra Cellular Therapies Inc | Organic compounds |
JP6051210B2 (ja) * | 2011-06-10 | 2016-12-27 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | 有機化合物 |
WO2013016662A1 (en) * | 2011-07-28 | 2013-01-31 | Memorial Sloan-Kettering Cancer Center | Diagnosis and treatment of parkinson's disease |
US9801882B2 (en) | 2013-02-17 | 2017-10-31 | Intra-Cellular Therapies, Inc. | Phosphodiesterase-1 inhibitors and their use in treatment of cardiovascular diseases |
EP2968338B1 (de) | 2013-03-15 | 2019-01-09 | Intra-Cellular Therapies, Inc. | Pde1-inhibitoren zur verwendung bei der behandlung und/oder prävention von zns-verletzungen und pns-krankheiten, störungen oder verletzungen |
CA2906640C (en) | 2013-03-15 | 2021-07-20 | Intra-Cellular Therapies, Inc. | Substituted imidazo-[1,2-a]pyrazolo[4.3-e]pyrimidin-4[5h]-one compounds and pharmaceutical compositions and use therof as pde1 inhibitors |
US9463186B2 (en) | 2013-04-15 | 2016-10-11 | Northwestern University | Treatment for dopaminergic disorders |
EP3091983B1 (de) | 2014-01-08 | 2019-10-02 | Intra-Cellular Therapies, Inc. | Pharmazeutische zusammensetzungen enthaltend einen pde-1-hemmer und einen pde-2-hemmer |
DK3157926T3 (da) | 2014-06-20 | 2019-08-19 | Intra Cellular Therapies Inc | Organiske forbindelser |
WO2016022893A1 (en) | 2014-08-07 | 2016-02-11 | Intra-Cellular Therapies, Inc. | Organic compounds |
US9546175B2 (en) | 2014-08-07 | 2017-01-17 | Intra-Cellular Therapies, Inc. | Organic compounds |
US10285992B2 (en) | 2014-08-07 | 2019-05-14 | Intra-Cellular Therapies, Inc. | Combinations of PDE1 inhibitors and NEP inhibitors and associated methods |
MX2017003646A (es) | 2014-09-17 | 2017-07-13 | Intra Cellular Therapies Inc | Compuestos y metodos. |
CN107205993B (zh) | 2014-12-06 | 2021-03-09 | 细胞内治疗公司 | 有机化合物 |
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JP2019510039A (ja) | 2016-03-28 | 2019-04-11 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | 新規組成物および方法 |
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JP7134168B6 (ja) | 2016-09-12 | 2024-02-02 | イントラ-セルラー・セラピーズ・インコーポレイテッド | 新規使用 |
US20200009213A1 (en) * | 2017-03-02 | 2020-01-09 | Universiteit Van Amsterdam | Specific Increase of Dopamine Synthesis THrough Targeting of the Guanylate Cyclase 2C Receptor in the Treatment of Parkinson's Disease |
EP3746081A4 (de) | 2018-01-31 | 2021-10-27 | Intra-Cellular Therapies, Inc. | Neuartige verwendungen |
JP2021535180A (ja) * | 2018-09-05 | 2021-12-16 | ユニベルシテイト ファン アムステルダム | パーキンソン病の処置の為のpde11又はpde2阻害剤の使用 |
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2001
- 2001-04-17 CN CN01811222A patent/CN1436080A/zh active Pending
- 2001-04-17 CA CA002407031A patent/CA2407031A1/en not_active Abandoned
- 2001-04-17 WO PCT/US2001/040538 patent/WO2001078711A2/en active IP Right Grant
- 2001-04-17 DE DE60124085T patent/DE60124085D1/de not_active Expired - Lifetime
- 2001-04-17 AU AU2001255849A patent/AU2001255849B8/en not_active Ceased
- 2001-04-17 AT AT01929063T patent/ATE343388T1/de not_active IP Right Cessation
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- 2001-04-17 US US09/836,744 patent/US20020006926A1/en not_active Abandoned
- 2001-11-21 US US09/989,672 patent/US6492371B2/en not_active Expired - Fee Related
Also Published As
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US20020077274A1 (en) | 2002-06-20 |
AU2001255849B2 (en) | 2005-12-22 |
AU2001255849B8 (en) | 2006-04-27 |
JP2004500425A (ja) | 2004-01-08 |
AU5584901A (en) | 2001-10-30 |
WO2001078711A2 (en) | 2001-10-25 |
CN1436080A (zh) | 2003-08-13 |
US6492371B2 (en) | 2002-12-10 |
DE60124085D1 (de) | 2006-12-07 |
CA2407031A1 (en) | 2001-10-25 |
EP1278522A2 (de) | 2003-01-29 |
EP1278522B1 (de) | 2006-10-25 |
WO2001078711A3 (en) | 2002-07-04 |
ATE343388T1 (de) | 2006-11-15 |
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