CZ188893A3 - The use of thrombin direct inhibitor for the preparation of medicaments with thrombolytic activity - Google Patents
The use of thrombin direct inhibitor for the preparation of medicaments with thrombolytic activity Download PDFInfo
- Publication number
- CZ188893A3 CZ188893A3 CZ931888A CZ188893A CZ188893A3 CZ 188893 A3 CZ188893 A3 CZ 188893A3 CZ 931888 A CZ931888 A CZ 931888A CZ 188893 A CZ188893 A CZ 188893A CZ 188893 A3 CZ188893 A3 CZ 188893A3
- Authority
- CZ
- Czechia
- Prior art keywords
- thrombolytic activity
- medicaments
- preparation
- direct inhibitor
- thrombin
- Prior art date
Links
- 230000002537 thrombolytic effect Effects 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 108090000190 Thrombin Proteins 0.000 title claims abstract description 4
- 239000003112 inhibitor Substances 0.000 title claims abstract description 4
- 229960004072 thrombin Drugs 0.000 title claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000003868 thrombin inhibitor Substances 0.000 claims description 9
- 229940123900 Direct thrombin inhibitor Drugs 0.000 claims description 8
- KWPACVJPAFGBEQ-IKGGRYGDSA-N (2s)-1-[(2r)-2-amino-3-phenylpropanoyl]-n-[(3s)-1-chloro-6-(diaminomethylideneamino)-2-oxohexan-3-yl]pyrrolidine-2-carboxamide Chemical group C([C@@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)CCl)C1=CC=CC=C1 KWPACVJPAFGBEQ-IKGGRYGDSA-N 0.000 claims description 5
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims description 4
- 229960003856 argatroban Drugs 0.000 claims description 4
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 7
- 230000017531 blood circulation Effects 0.000 description 4
- 239000003527 fibrinolytic agent Substances 0.000 description 4
- 229960000103 thrombolytic agent Drugs 0.000 description 4
- FXFYPTZERULUBS-SQNIBIBYSA-N Ac-(D)Phe-Pro-boroArg-OH Chemical compound C([C@@H](NC(=O)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)B(O)O)C1=CC=CC=C1 FXFYPTZERULUBS-SQNIBIBYSA-N 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 108010075065 acetylphenylalanyl-prolyl-boroarginine Proteins 0.000 description 3
- 108010001014 Plasminogen Activators Proteins 0.000 description 2
- 102000001938 Plasminogen Activators Human genes 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 210000000702 aorta abdominal Anatomy 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 229940127126 plasminogen activator Drugs 0.000 description 2
- 210000002254 renal artery Anatomy 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 206010058178 Aortic occlusion Diseases 0.000 description 1
- 206010003178 Arterial thrombosis Diseases 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010038563 Reocclusion Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 230000001732 thrombotic 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
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Použití přímého inhibitoru trombinu pro výrobxr/léčiva s trombólytickou účinností
Oblast techniky
Vynález se týká použití přímého inhibitoru trombinu pro výrobu léčiva s trombolytickou účinností.
Dosavadní stav techniky
Sloučeniny, které inhibují trombin interakcí s aktivním místem této proteázy, se používají jako antitrombotická činidla nebo je v případě některých sloučenin takové použití ve stádiu vývoje. Příklady takových sloučenin jsou argatroban (Okamoto S. a kol., Biochem. Res. Commun. 101, 440, 1981 a jinde), produkt PPACK (Kettner C.A- a Shaw E.N., Thromb. Res. 14, 969, 1779 a jinde), produkt DUP 714 (Kettner C.A. a kol., J. Biol. Chem. 265, 18289, 1990 a jinde) a hirudiny (Rydel T.J. a kol., Science 245, 277, 1989 a jinde).
V případě infarktu myokardu, arteriální nebo venální trombózy nebo-.plicní embolie mohou inhibitory trombinu urychlit lyži a zamezit reokluzi po léčení exogenním trombolytickým činidlem, jakým je aktivátor rekombinantního plasminogenu (rTPA) nebo streptokináza.
Podstata vynálezu
V rámci vynálezu byla studována účinnost přímých inhibitorů trombinu jako takových ve funkci trombolytických činidel v nepřítomnosti exogenních plasminogenních aktivátorů.
Sloučeniny použitelné podle vynálezu byly studovány na krysách za účelem stanovení jejich účinnosti jako trombolytických činidel za použití modelu okluzní trombózy aorty indukované elektrickou stimulací.
Krysy CD s tělesnou hmotností 450 až 500 g se anestetizují pentobarbitalem sodným (60 mg/kg intraperitoneálně), načež se jim zavede katétr do levé renální arterie. Trombóza se indukuje metodou popsanou Hladovcem (Thromb. Haemosts., (1971), 26, 407-410). Obnaží se segment abdominální aorty dlouhý asi 1 cm mezi renální arterií a kyčelním rozvětvením, načež se zde umístí elektromagnetická sonda pro měření průtoku krve a ve směru toku krve ještě bipolární elektroda. Po 15 minutové stabilizační periodě se na vnější povrch arterie přímo zavádí pomocí stimulátoru po dobu 5 minut proud 5 mA. Když krevní průtok dosáhne nulové hodnoty, která byla předběžně stanovena sevřením arterie mezi sondou a elektrodou, zaznamená se čas vzniku trombotické okluze. Po 5 minutách stabilizace trombu, se katétrem injikuje testovaná sloučenina nebo vehikulum v 0,5 ml dávce a potom následuje 60 minutová perfuze při průtoku 0,1 ml/min. Po dobu perfuze se zaznamená krevní průtok. Trombolýza se vyhodnotí měřením plochy pod křivkou, která závisí na času nezbytném k dosažení opětovné rekanalizace a na míře této rekanalizace. Výsledky se vyjádří jako průměrné hodnoty + střední standardní odchylka.
U pokusných zvířat, kterým se zavádí pouze vehikulum, zůstává abdominální aorta ucpána po celou dobu podávání vehikula. Naproti tomu zvyšují přímé inhibitory trombinu v závislosti na dávce inhibitoru plochu pod křivkou a rychle restaurují krevní průtok.
v rámci.vynálezu byly zejména testovány následující látky: argatroban, Phe-Pro-Arg-chlormethylketon (PPACK) a Ac-(D-Phe)Pro-boro-Arg-OH (DUP 714) vzorce 1
které vykazovaly trombolytickou účinnost.
Získané výsledky jsou uvedeny v následující tabulce.
olytický účinek produktů argatroban, PPACK a DUP 714
+)
P
0) s
c a
M φ
tfl •H b
S <u 0)
H
Jd
Ή
X!
ϋ •Η .05, ** p < 0.01 versus test .05, ffff p < 0.01 versus test = střední standardní odchylka ο ο
V V
Λ α * cn *
m
Uvedené výsledky ukazují, že přímé inhibitory trombinu mohou být použity pro výrobu léčiv s trombolytickou účinností.
Tyto inhibitory mohou být použity při patologických stavech, u kterých se používají trombolytická činidla, jakými jsou infarkt myokardu, zánět tepen spodních okončetin, rozsáhlá venál ní trombóza a plicní embolie.
Za tímto účelem mohou být uvedené látky formulovány do všech farmaceutických forem, které jsou vhodné pro intravenózní podání, v kombinaci s příslušnými farmaceutickými pomocnými látkami a v dávkách, umožňujících denní podání 10 až 500 mg účinné látky.
Claims (4)
- PATENTOVÉNÁROKY1. Použití inhibitoru působícího na aktivní místo trombinu pro výrobu léčiva s trombolytickou účinností.
- 2. Použití podle nároku přímým inhibitorem trombinu1, vyznačené je argatroban.tím, že
- 3. Použití podle nároku přímým inhibitorem trombinu1,vyznačen& tím, že je Phe-Pro-Arg-chlormethylketon.
- 4. Použití podle nároku přímým inhibitorem trombinu1,vyznačené tím, že je Ac-(D-Phe)-Pro-boro-Arg-OH.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9210833A FR2695562B1 (fr) | 1992-09-11 | 1992-09-11 | Utilisation d'un inhibiteur direct de la thrombine pour la fabrication d'un médicament à activité thrombolytique. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CZ188893A3 true CZ188893A3 (en) | 1994-03-16 |
Family
ID=9433400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ931888A CZ188893A3 (en) | 1992-09-11 | 1993-09-10 | The use of thrombin direct inhibitor for the preparation of medicaments with thrombolytic activity |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5583113A (cs) |
| EP (1) | EP0589741B1 (cs) |
| JP (1) | JPH06228007A (cs) |
| KR (1) | KR100261526B1 (cs) |
| CN (1) | CN1066961C (cs) |
| AT (1) | ATE163856T1 (cs) |
| AU (1) | AU4628193A (cs) |
| CA (1) | CA2105888C (cs) |
| CZ (1) | CZ188893A3 (cs) |
| DE (1) | DE69317343T2 (cs) |
| DK (1) | DK0589741T3 (cs) |
| ES (1) | ES2115741T4 (cs) |
| FR (1) | FR2695562B1 (cs) |
| IL (1) | IL106981A (cs) |
| NO (1) | NO306537B1 (cs) |
| SK (1) | SK96993A3 (cs) |
| TW (1) | TW284691B (cs) |
| ZA (1) | ZA936707B (cs) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5830448A (en) * | 1994-06-16 | 1998-11-03 | Genentech, Inc. | Compositions and methods for the treatment of tumors |
| DE4421052A1 (de) | 1994-06-17 | 1995-12-21 | Basf Ag | Neue Thrombininhibitoren, ihre Herstellung und Verwendung |
| US6030972A (en) * | 1995-02-17 | 2000-02-29 | Basf Aktiengesellschaft | Dipeptide amidines as thrombin inhibitors |
| SA96170106A (ar) * | 1995-07-06 | 2005-12-03 | أسترا أكتيبولاج | مشتقات حامض أميني جديدة |
| US5840733A (en) | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| WO1999037668A1 (de) | 1998-01-26 | 1999-07-29 | Basf Aktiengesellschaft | Thrombininhibitoren |
| CN101598725B (zh) * | 2009-06-23 | 2012-07-18 | 南通大学附属医院 | 阿加曲班在血细胞和生化常规分析中的应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4258192A (en) * | 1977-12-16 | 1981-03-24 | Mitsubishi Chemical Industries Limited | N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof |
| US4318904A (en) * | 1980-04-25 | 1982-03-09 | Research Corporation | Peptide affinity labels for thrombin and other trypsin-like proteases |
| US4929602A (en) * | 1987-11-25 | 1990-05-29 | Scripps Clinic And Research Foundation | Method of inhibiting platelet dependent arterial thrombosis |
| US5196404B1 (en) * | 1989-08-18 | 1996-09-10 | Biogen Inc | Inhibitors of thrombin |
-
1992
- 1992-09-11 FR FR9210833A patent/FR2695562B1/fr not_active Expired - Fee Related
-
1993
- 1993-09-02 EP EP93402136A patent/EP0589741B1/fr not_active Expired - Lifetime
- 1993-09-02 AT AT93402136T patent/ATE163856T1/de not_active IP Right Cessation
- 1993-09-02 DE DE69317343T patent/DE69317343T2/de not_active Expired - Lifetime
- 1993-09-02 ES ES93402136T patent/ES2115741T4/es not_active Expired - Lifetime
- 1993-09-02 DK DK93402136T patent/DK0589741T3/da active
- 1993-09-10 IL IL10698193A patent/IL106981A/en not_active IP Right Cessation
- 1993-09-10 TW TW082107438A patent/TW284691B/zh active
- 1993-09-10 CZ CZ931888A patent/CZ188893A3/cs unknown
- 1993-09-10 SK SK969-93A patent/SK96993A3/sk unknown
- 1993-09-10 AU AU46281/93A patent/AU4628193A/en not_active Abandoned
- 1993-09-10 JP JP5225606A patent/JPH06228007A/ja active Pending
- 1993-09-10 NO NO933235A patent/NO306537B1/no not_active IP Right Cessation
- 1993-09-10 KR KR1019930018230A patent/KR100261526B1/ko not_active Expired - Lifetime
- 1993-09-10 ZA ZA936707A patent/ZA936707B/xx unknown
- 1993-09-10 CA CA002105888A patent/CA2105888C/fr not_active Expired - Lifetime
- 1993-09-10 CN CN93117197A patent/CN1066961C/zh not_active Expired - Lifetime
-
1995
- 1995-02-13 US US08/387,382 patent/US5583113A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2105888A1 (fr) | 1994-03-12 |
| SK96993A3 (en) | 1994-08-10 |
| ATE163856T1 (de) | 1998-03-15 |
| NO933235D0 (no) | 1993-09-10 |
| FR2695562A1 (fr) | 1994-03-18 |
| EP0589741A1 (fr) | 1994-03-30 |
| CA2105888C (fr) | 2008-04-15 |
| IL106981A (en) | 1999-03-12 |
| KR100261526B1 (ko) | 2000-07-15 |
| US5583113A (en) | 1996-12-10 |
| IL106981A0 (en) | 1993-12-28 |
| ES2115741T4 (es) | 2012-07-04 |
| CN1087015A (zh) | 1994-05-25 |
| JPH06228007A (ja) | 1994-08-16 |
| KR940006600A (ko) | 1994-04-25 |
| DE69317343D1 (de) | 1998-04-16 |
| DK0589741T3 (da) | 1998-12-21 |
| EP0589741B1 (fr) | 1998-03-11 |
| FR2695562B1 (fr) | 1994-10-14 |
| NO933235L (no) | 1994-03-14 |
| CN1066961C (zh) | 2001-06-13 |
| ES2115741T3 (es) | 1998-07-01 |
| NO306537B1 (no) | 1999-11-22 |
| AU4628193A (en) | 1994-03-17 |
| TW284691B (cs) | 1996-09-01 |
| DE69317343T2 (de) | 1998-10-08 |
| ZA936707B (en) | 1994-03-30 |
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