CA2170278C - Inhibition of smooth muscle cell migration by (r)-amlodipine - Google Patents
Inhibition of smooth muscle cell migration by (r)-amlodipineInfo
- Publication number
- CA2170278C CA2170278C CA002170278A CA2170278A CA2170278C CA 2170278 C CA2170278 C CA 2170278C CA 002170278 A CA002170278 A CA 002170278A CA 2170278 A CA2170278 A CA 2170278A CA 2170278 C CA2170278 C CA 2170278C
- Authority
- CA
- Canada
- Prior art keywords
- amlodipine
- isomer
- smooth muscle
- pharmaceutically acceptable
- muscle cell
- 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.)
- Expired - Fee Related
Links
- 230000015590 smooth muscle cell migration Effects 0.000 title claims abstract description 21
- 230000005764 inhibitory process Effects 0.000 title claims description 16
- HTIQEAQVCYTUBX-QGZVFWFLSA-N (R)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-QGZVFWFLSA-N 0.000 title description 5
- 229960000528 amlodipine Drugs 0.000 claims abstract description 31
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 230000008061 calcium-channel-blocking effect Effects 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 12
- 210000004509 vascular smooth muscle cell Anatomy 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 7
- 238000002399 angioplasty Methods 0.000 abstract description 6
- 208000031481 Pathologic Constriction Diseases 0.000 abstract description 4
- 208000037804 stenosis Diseases 0.000 abstract description 4
- 201000009273 Endometriosis Diseases 0.000 abstract description 3
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000480 calcium channel blocker Substances 0.000 description 9
- 229940127291 Calcium channel antagonist Drugs 0.000 description 7
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- TZNOWAJJWCGILX-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl TZNOWAJJWCGILX-BTJKTKAUSA-N 0.000 description 1
- NWDQBIRZEWCIMO-UHFFFAOYSA-N 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethyl-5,6-dimethylpiperidine-3,5-dicarboxylic acid Chemical compound CCC1(C(O)=O)C(COCCN)NC(C)C(C)(C(O)=O)C1C1=CC=CC=C1Cl NWDQBIRZEWCIMO-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000003433 aortic smooth muscle cell Anatomy 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- 230000008692 neointimal formation Effects 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- 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
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- 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
- A61P9/08—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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines Containing Plant Substances (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The R(+) isomer of amlodipine is a potent inhibitor of smooth muscle cell migration despite its lack of calcium channel-blocking activity. It is useful for treating atherosclerosis, re-stenosis after angioplasty and endometriosis.
Description
WO 95l05822 PCT/EP94/02697 INHIBITION OF SMOOTH MUSCLE CELL MIGRATION BY (R)-AMLODIPINE
This invention relates to treatment of medical conditions involving smooth muscle cell migration using the R(+) isomer of 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, a compound having the approved non-proprietary name "amlodipine".
Amlodipine is a known calcium channel-blocking agent having vasodilatory activity and is currently used, generally in the form of a pharmaceutically acceptable salt such as its maleate or bezylate, in treatment of hypertension and angina. The compound and its preparation are described in European patent 0089167 B1.
Amlodipine is a racemic compound due to its symmetry at position 4 of the dihydropyridine ring and the R- and S-enantiomers may be prepared by methods described in J.
Med. Chem. 1986 29 1696 (Arrowsmith et al.) and European Patent Application 0331315 A. It was formerly believed that the two resolved enantiomers consisted of the R-(-) and S-(+) isomers but it has subsequently been found that these are in fact the S(-) and the R(+) isomer, respectively (see J. Med. Chem., 35, 3341-3344 (1992), Goldmann et al.). It is known that the calcium channel blocking activity of amlodipine is substantially confined to the S(-) form and the racemic mixture of R(+) and S(-) forms; the R(+) isomer has little or no calcium channel blocking activity and so is not likely to have significant cardiovascular effects when administered to a patient.
SUBSTITUTE SHEET (RULE 2G) ..
This invention relates to treatment of medical conditions involving smooth muscle cell migration using the R(+) isomer of 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, a compound having the approved non-proprietary name "amlodipine".
Amlodipine is a known calcium channel-blocking agent having vasodilatory activity and is currently used, generally in the form of a pharmaceutically acceptable salt such as its maleate or bezylate, in treatment of hypertension and angina. The compound and its preparation are described in European patent 0089167 B1.
Amlodipine is a racemic compound due to its symmetry at position 4 of the dihydropyridine ring and the R- and S-enantiomers may be prepared by methods described in J.
Med. Chem. 1986 29 1696 (Arrowsmith et al.) and European Patent Application 0331315 A. It was formerly believed that the two resolved enantiomers consisted of the R-(-) and S-(+) isomers but it has subsequently been found that these are in fact the S(-) and the R(+) isomer, respectively (see J. Med. Chem., 35, 3341-3344 (1992), Goldmann et al.). It is known that the calcium channel blocking activity of amlodipine is substantially confined to the S(-) form and the racemic mixture of R(+) and S(-) forms; the R(+) isomer has little or no calcium channel blocking activity and so is not likely to have significant cardiovascular effects when administered to a patient.
SUBSTITUTE SHEET (RULE 2G) ..
It is known~that calcium channel blockers in general tend to inhibit smooth muscle cell migration. Thus they have been found to impede lesion development in various animal models of atherosclerosis (see Arteriosclerosis 5;
250 (1985), Willis et al., Arteriosclerosis 6; 237 (1986), Sugano et al.); also smooth muscle cell proliferative lesions following endothelial cell damage by balloon angioplasty are reduced y Isradipine, a calcium channel blocker (see Am. J. Pathol 124, 88-93 (1986) Handley et al.). During restenosis following balloon angioplasty and atherogenesis, vascular smooth muscle cells migrate from the media to the intima where they proliferate. It is believed that the efficacy of calcium channel blockers in animal models of re-stenosis post-balloon angioplasty and atherosclerosis is due to inhibition of vascular smooth muscle cell migration and subsequent reduction in smooth muscle cell proliferation and neointimal formation.
Thus, calcium channel blockers would be expected to be useful in the treatment of conditions of smooth muscle cell migration, including atherosclerosis, re-stenosis after angioplasty and endometriosis.
It has now been discovered, surprisingly and contrary to a11 existing theory, that the R(+) isomer of amlodipine, despite its lack of calcium channel-blocking activity, is a potent inhibitor of smooth muscle cell migration and its potency in this respect is greater that of the S(-) isomer of amlodipine and some other known calcium channel-blockers. The R(+) isomer thus provides SUBSTITUTE SHEET (RULE 26) a means of treating conditions involving smooth muscle cell migration without any concomitant cardiovascular effects.
It is therefore applicable to patients for whom reduction of blood pressure would be undesirable.
Thus, one aspect of the invention comprises the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
The invention also provides use of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for making a medicament for treatment of conditions requiring inhibition of smooth muscle cell migration.
A further aspect of the invention provides a pharm-aceutical composition comprising the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceu-tically acceptable carrier or diluent, said composition being substantially free of calcium channel-blocking activity.
Yet a further aspect of the invention provides a commercial package containing the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof) together with instructions for its use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
The invention also provides a method of treating conditions requiring inhibition of smooth muscle cell migration which comprises administering to the patient an A
_ 21 70 278 effective amount of the R(+) isomer of amlodipine or a pharm-aceutically acceptable salt thereof.
The pharmaceutically acceptable salts of amlodipine include the maleate and the bezylate. The conditions to - 3a -be treated inclu3e atherosclerosis, incipient re-stenosis following angioplasty, and endometriosis. The R(+) isomer of amlodipine may be used in the absence of the S(-) isomer and of any other compound acting as a calcium channel-blocker.
The effect of the R(+) isomer of amlodipine on smooth muscle cell migration was demonstrated using an aortic explant assay method in which the modulation, migration and proliferation of smooth muscle cells are assessed using primary cultures of rabbit aortic smooth muscle cells as described in Atherosclerosis 86 227-237 (1191). In this method uniform pieces of intimal/medial tissue from rabbit aorta were cultured in individual wells of a well plate. Migration was induced by addition of platelet-derived growth factor to the culture.
Following a lag phase of several days the smooth muscle cells migrated from the explanted tissue and proliferated.
The distance covered by the outgrowing smooth muscle cells was measured.
This assay was carried out with varying concentrations of test compound added to the culture.
The compounds thus tested were the maleate salts of the racemic mixture of R(+) and S(-) amlodipine, the maleate salts of R(+) and S(-) amlodipine separately and the known calcium channel-blocking agents nitrendipine and verapamil.
SuBST~TUTE SHEET (RULE 26) The results obtained are shown in Table 1, in which the percentage inhibition of smooth muscle cell migration for concentrations of test compound of 1 nanomole and 0.1 nanomole are recorded.
The racemic, R(+) and S(-) forms of amlodipine maleate were also tested for inhibition of R+-induced rat aortic contraction by the method described by Burges et al, J. Cardiovasc Pharmacol 9(1) 110-9; The 1C5~ (50g inhibitory concentration) values in nanomoles are also recorded in Table 1 and afford a measure of calcium channel-blocking activity.
o inhibition inhibition of of SMC
migration R+ induced rat from explants aortic contraction Compound 1nM 0 .1nM 1C5 ( nM ) Amlodipine 33 39 2 (racemate) Amlodipine 39 36 1000 R(+) Amlodipine 30 21 1 S(-) Nitrendipine 28 14 Verapamil 22 13 It is evident from these results that the R(+) enantiomer of amlopidine is effective in inhibiting smooth muscle cell migration even though its activity as a calcium channel blocker is negligible.
For administration to man in the curative or SUBSTITUTE SHEET (RULE 26) WO 95I05822 PCTlEP94/02697 ~17U2'~8 prophylactic treatment of conditions involving smooth muscle migration, oral doses of R(+) amlodipine or its salts may be in the range of 2-10 mg daily for an average adult patient (weighing 70 kg), that is a range similar to that used for amlodipine in the treatment of hypertension. However, the absence of cardiovascular effects allows administration of much larger doses than would be recommended for the calcium channel-blocking S(-) isomer or the racemate, with a correspondingly greater effect on cell migration. The oral dose of R(+) amlodipine or a salt thereof for the average adult patient may thus be 20mg or more and up to 100mg/day, or even greater. The actual dose used will be determined by a physician considering the age, weight, condition and medical history of the patient. For a typical adult patient individual tablets or capsules are likely to contain 1 to 100mg of active compound, in a suitable pharmaceutical vehicle or carrier. Dosages for intravenous administration would be in the range of 1-20mg of active compound per single dose as required.
Thus, according to another aspect of the invention, there is provided a unit dose of a pharmaceutical composition substantially free of calcium channel-blocking activity containing (for oral administration) from lmg to 100mg, preferably 20 to 100mg, of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof. A further aspect of the invention provides such a unit dose for intravenous administration containing from 1 to 20mg of the R(+) isomer of amlodipine or salt thereof.
S!lBSTITU T E SHEET (RULE 26)
250 (1985), Willis et al., Arteriosclerosis 6; 237 (1986), Sugano et al.); also smooth muscle cell proliferative lesions following endothelial cell damage by balloon angioplasty are reduced y Isradipine, a calcium channel blocker (see Am. J. Pathol 124, 88-93 (1986) Handley et al.). During restenosis following balloon angioplasty and atherogenesis, vascular smooth muscle cells migrate from the media to the intima where they proliferate. It is believed that the efficacy of calcium channel blockers in animal models of re-stenosis post-balloon angioplasty and atherosclerosis is due to inhibition of vascular smooth muscle cell migration and subsequent reduction in smooth muscle cell proliferation and neointimal formation.
Thus, calcium channel blockers would be expected to be useful in the treatment of conditions of smooth muscle cell migration, including atherosclerosis, re-stenosis after angioplasty and endometriosis.
It has now been discovered, surprisingly and contrary to a11 existing theory, that the R(+) isomer of amlodipine, despite its lack of calcium channel-blocking activity, is a potent inhibitor of smooth muscle cell migration and its potency in this respect is greater that of the S(-) isomer of amlodipine and some other known calcium channel-blockers. The R(+) isomer thus provides SUBSTITUTE SHEET (RULE 26) a means of treating conditions involving smooth muscle cell migration without any concomitant cardiovascular effects.
It is therefore applicable to patients for whom reduction of blood pressure would be undesirable.
Thus, one aspect of the invention comprises the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
The invention also provides use of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for making a medicament for treatment of conditions requiring inhibition of smooth muscle cell migration.
A further aspect of the invention provides a pharm-aceutical composition comprising the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceu-tically acceptable carrier or diluent, said composition being substantially free of calcium channel-blocking activity.
Yet a further aspect of the invention provides a commercial package containing the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof) together with instructions for its use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
The invention also provides a method of treating conditions requiring inhibition of smooth muscle cell migration which comprises administering to the patient an A
_ 21 70 278 effective amount of the R(+) isomer of amlodipine or a pharm-aceutically acceptable salt thereof.
The pharmaceutically acceptable salts of amlodipine include the maleate and the bezylate. The conditions to - 3a -be treated inclu3e atherosclerosis, incipient re-stenosis following angioplasty, and endometriosis. The R(+) isomer of amlodipine may be used in the absence of the S(-) isomer and of any other compound acting as a calcium channel-blocker.
The effect of the R(+) isomer of amlodipine on smooth muscle cell migration was demonstrated using an aortic explant assay method in which the modulation, migration and proliferation of smooth muscle cells are assessed using primary cultures of rabbit aortic smooth muscle cells as described in Atherosclerosis 86 227-237 (1191). In this method uniform pieces of intimal/medial tissue from rabbit aorta were cultured in individual wells of a well plate. Migration was induced by addition of platelet-derived growth factor to the culture.
Following a lag phase of several days the smooth muscle cells migrated from the explanted tissue and proliferated.
The distance covered by the outgrowing smooth muscle cells was measured.
This assay was carried out with varying concentrations of test compound added to the culture.
The compounds thus tested were the maleate salts of the racemic mixture of R(+) and S(-) amlodipine, the maleate salts of R(+) and S(-) amlodipine separately and the known calcium channel-blocking agents nitrendipine and verapamil.
SuBST~TUTE SHEET (RULE 26) The results obtained are shown in Table 1, in which the percentage inhibition of smooth muscle cell migration for concentrations of test compound of 1 nanomole and 0.1 nanomole are recorded.
The racemic, R(+) and S(-) forms of amlodipine maleate were also tested for inhibition of R+-induced rat aortic contraction by the method described by Burges et al, J. Cardiovasc Pharmacol 9(1) 110-9; The 1C5~ (50g inhibitory concentration) values in nanomoles are also recorded in Table 1 and afford a measure of calcium channel-blocking activity.
o inhibition inhibition of of SMC
migration R+ induced rat from explants aortic contraction Compound 1nM 0 .1nM 1C5 ( nM ) Amlodipine 33 39 2 (racemate) Amlodipine 39 36 1000 R(+) Amlodipine 30 21 1 S(-) Nitrendipine 28 14 Verapamil 22 13 It is evident from these results that the R(+) enantiomer of amlopidine is effective in inhibiting smooth muscle cell migration even though its activity as a calcium channel blocker is negligible.
For administration to man in the curative or SUBSTITUTE SHEET (RULE 26) WO 95I05822 PCTlEP94/02697 ~17U2'~8 prophylactic treatment of conditions involving smooth muscle migration, oral doses of R(+) amlodipine or its salts may be in the range of 2-10 mg daily for an average adult patient (weighing 70 kg), that is a range similar to that used for amlodipine in the treatment of hypertension. However, the absence of cardiovascular effects allows administration of much larger doses than would be recommended for the calcium channel-blocking S(-) isomer or the racemate, with a correspondingly greater effect on cell migration. The oral dose of R(+) amlodipine or a salt thereof for the average adult patient may thus be 20mg or more and up to 100mg/day, or even greater. The actual dose used will be determined by a physician considering the age, weight, condition and medical history of the patient. For a typical adult patient individual tablets or capsules are likely to contain 1 to 100mg of active compound, in a suitable pharmaceutical vehicle or carrier. Dosages for intravenous administration would be in the range of 1-20mg of active compound per single dose as required.
Thus, according to another aspect of the invention, there is provided a unit dose of a pharmaceutical composition substantially free of calcium channel-blocking activity containing (for oral administration) from lmg to 100mg, preferably 20 to 100mg, of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof. A further aspect of the invention provides such a unit dose for intravenous administration containing from 1 to 20mg of the R(+) isomer of amlodipine or salt thereof.
S!lBSTITU T E SHEET (RULE 26)
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
2. Use of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for making a medicament for treatment of conditions requiring inhibition of smooth muscle cell migration.
3. Use of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof for treatment of conditions requiring inhibition of smooth muscle cell migration.
4. A pharmaceutical composition for use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration, comprising an effective amount of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said composition being substantially free of calcium channel-blocking activity.
5. A unit dose of a composition according to claim 4, for oral administration, containing from 1 mg to 100 mg of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof.
6. A unit dose according to claim 5, containing at least 20 mg of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof.
7. A unit dose of a composition according to claim 4 for intravenous administration, containing from 1 mg to 20 mg of the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof.
8. A commercial package containing, as active pharmaceutical ingredient, the R(+) isomer of amlodipine or a pharmaceutically acceptable salt thereof, together with instructions for its use in the treatment of conditions requiring inhibition of vascular smooth muscle cell migration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9317773.1 | 1993-08-26 | ||
| GB939317773A GB9317773D0 (en) | 1993-08-26 | 1993-08-26 | Therapeutic compound |
| PCT/EP1994/002697 WO1995005822A1 (en) | 1993-08-26 | 1994-08-10 | Inhibition of smooth muscle cell migration by (r)-amlodipine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2170278A1 CA2170278A1 (en) | 1995-03-02 |
| CA2170278C true CA2170278C (en) | 1999-08-03 |
Family
ID=10741080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002170278A Expired - Fee Related CA2170278C (en) | 1993-08-26 | 1994-08-10 | Inhibition of smooth muscle cell migration by (r)-amlodipine |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US6080761A (en) |
| EP (1) | EP0754043B1 (en) |
| JP (2) | JP3007992B2 (en) |
| KR (1) | KR0163840B1 (en) |
| CN (1) | CN1060039C (en) |
| AT (1) | ATE192337T1 (en) |
| AU (1) | AU686658B2 (en) |
| CA (1) | CA2170278C (en) |
| DE (1) | DE69424317T2 (en) |
| DK (1) | DK0754043T3 (en) |
| ES (1) | ES2145149T3 (en) |
| GB (1) | GB9317773D0 (en) |
| GR (1) | GR3033547T3 (en) |
| IL (1) | IL110700A (en) |
| NO (1) | NO308826B1 (en) |
| NZ (1) | NZ271993A (en) |
| PT (1) | PT754043E (en) |
| TW (1) | TW470646B (en) |
| WO (1) | WO1995005822A1 (en) |
| ZA (1) | ZA946475B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7129265B2 (en) * | 1999-04-23 | 2006-10-31 | Mason R Preston | Synergistic effects of amlodipine and atorvastatin metabolite as a basis for combination therapy |
| GB0020842D0 (en) | 2000-08-23 | 2000-10-11 | Pfizer Ltd | Therapeutic compositions |
| US6737430B2 (en) | 2000-11-09 | 2004-05-18 | Pfizer, Inc. | Mutual prodrug of amlodipine and atorvastatin |
| AT5874U1 (en) * | 2000-12-29 | 2003-01-27 | Bioorg Bv | PHARMACEUTICAL PREPARATIONS CONTAINING AMLODIPINMALEAT |
| WO2002053535A2 (en) * | 2000-12-29 | 2002-07-11 | Bioorganics B.V. | Process for making amlodipine, derivatives thereof, and precursors therefor |
| US7335380B2 (en) | 2000-12-29 | 2008-02-26 | Synthon Ip Inc. | Amlodipine free base |
| CN1152013C (en) * | 2001-11-22 | 2004-06-02 | 张喜田 | Levo-amlodipine salt able to generate hydrate and its hydrate and preparation |
| ES2307209T3 (en) * | 2004-10-20 | 2008-11-16 | Emcure Pharmaceuticals Limited | PROCEDURE FOR THE PRODUCTION OF AN AMLODIPINE CHARMER WITH A HIGH OPTIC PURITY. |
| KR100828883B1 (en) * | 2006-10-27 | 2008-05-09 | 씨제이제일제당 (주) | Separation Method of S-(-)-Amlodipine from Racemic Amlodipine |
| KR100830003B1 (en) * | 2006-10-31 | 2008-05-15 | 씨제이제일제당 (주) | Crystalline S-(-)-Amlodipine Adipic Acid Anhydride and Method for Preparing the Same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8804630D0 (en) * | 1988-02-27 | 1988-03-30 | Pfizer Ltd | Preparation of r-& s-amlodipine |
| GB9405833D0 (en) * | 1994-03-24 | 1994-05-11 | Pfizer Ltd | Separation of the enantiomers of amlodipine |
-
1993
- 1993-08-26 GB GB939317773A patent/GB9317773D0/en active Pending
-
1994
- 1994-08-10 ES ES94926189T patent/ES2145149T3/en not_active Expired - Lifetime
- 1994-08-10 DE DE69424317T patent/DE69424317T2/en not_active Expired - Fee Related
- 1994-08-10 EP EP94926189A patent/EP0754043B1/en not_active Expired - Lifetime
- 1994-08-10 CN CN94193173A patent/CN1060039C/en not_active Expired - Fee Related
- 1994-08-10 NZ NZ271993A patent/NZ271993A/en unknown
- 1994-08-10 KR KR1019960700919A patent/KR0163840B1/en not_active Expired - Fee Related
- 1994-08-10 CA CA002170278A patent/CA2170278C/en not_active Expired - Fee Related
- 1994-08-10 WO PCT/EP1994/002697 patent/WO1995005822A1/en not_active Ceased
- 1994-08-10 DK DK94926189T patent/DK0754043T3/en active
- 1994-08-10 US US08/596,365 patent/US6080761A/en not_active Expired - Fee Related
- 1994-08-10 PT PT94926189T patent/PT754043E/en unknown
- 1994-08-10 JP JP7507319A patent/JP3007992B2/en not_active Expired - Lifetime
- 1994-08-10 AT AT94926189T patent/ATE192337T1/en not_active IP Right Cessation
- 1994-08-10 AU AU76129/94A patent/AU686658B2/en not_active Ceased
- 1994-08-18 IL IL11070094A patent/IL110700A/en not_active IP Right Cessation
- 1994-08-19 TW TW083107624A patent/TW470646B/en not_active IP Right Cessation
- 1994-08-25 ZA ZA946475A patent/ZA946475B/en unknown
-
1996
- 1996-02-23 NO NO960730A patent/NO308826B1/en unknown
-
1999
- 1999-07-23 JP JP11208778A patent/JP2000044475A/en active Pending
-
2000
- 2000-05-31 GR GR20000401239T patent/GR3033547T3/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NZ271993A (en) | 1997-11-24 |
| KR960703593A (en) | 1996-08-31 |
| IL110700A (en) | 1999-04-11 |
| CA2170278A1 (en) | 1995-03-02 |
| GB9317773D0 (en) | 1993-10-13 |
| NO960730L (en) | 1996-02-23 |
| GR3033547T3 (en) | 2000-09-29 |
| DE69424317T2 (en) | 2000-08-24 |
| ZA946475B (en) | 1996-02-26 |
| US6080761A (en) | 2000-06-27 |
| KR0163840B1 (en) | 1998-12-01 |
| WO1995005822A1 (en) | 1995-03-02 |
| PT754043E (en) | 2000-09-29 |
| IL110700A0 (en) | 1994-11-11 |
| NO960730D0 (en) | 1996-02-23 |
| DK0754043T3 (en) | 2000-08-07 |
| EP0754043B1 (en) | 2000-05-03 |
| AU7612994A (en) | 1995-03-21 |
| EP0754043A1 (en) | 1997-01-22 |
| JPH08509004A (en) | 1996-09-24 |
| CN1129907A (en) | 1996-08-28 |
| ES2145149T3 (en) | 2000-07-01 |
| ATE192337T1 (en) | 2000-05-15 |
| NO308826B1 (en) | 2000-11-06 |
| JP2000044475A (en) | 2000-02-15 |
| JP3007992B2 (en) | 2000-02-14 |
| CN1060039C (en) | 2001-01-03 |
| TW470646B (en) | 2002-01-01 |
| AU686658B2 (en) | 1998-02-12 |
| DE69424317D1 (en) | 2000-06-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20130812 |