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US5196404A
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Inhibitors of thrombin
Assignee: Biogen MA Inc
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Filing: 1990-07-06
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Granted: 1993-03-23
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Expires: 2010-07-06
Abstract
Abstract This invention relates to novel biologically active molecules which bind to and inhibit thrombin. Specifically, these molecules are characterized by a thrombin anion-binding exosite association moiety (ABEAM); a linker portion of at least 18 ANGSTROM in length; and a thrombin catalytic site-directed moiety (CSDM). This invention also relates to compositions, combinations and methods which employ these molecules for therapeutic, prophylactic and diagnostic purposes.
Inventors
- 👤 John M. Maraganore
- 👤 II John W. Fenton
- 👤 Toni Kline
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-24 16:42
CPC Classifications
C; C07; C07K; C07K14/00; C07K7/00; C07K7/02; A; A61; A61P; A61P29/00; A61P35/00; A61P7/00; A61P7/02; C07K14/81; C07K14/815; A61K; A61K38/00; Y; Y10; Y10S; Y10S436/00; Y10S436/804; Y10S623/00; Y10S623/92
Claims Analysis
Total Claims: 38
Claim 1
Independent Claim
223 words
A thrombin inhibitor consisting of: a) a catalystic site-directed moiety that binds to and inhibits the active site of thrombin; wherein said catalytic site-directed moiety is selected from serine proteinase inhibitors, heterocyclic protease inhibitors, thrombin-specific inhibitors, transition state analogues, benzamidine, DAPA, NAPAP, argipidine, or moieties of the formulae: X--A.sub.1 --A.sub.2 --A.sub.3 --Y or X--C.sub.1 --C.sub.2 --A.sub.3 --Y, wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 35 atoms; A 1 is Arg, Lys or Orn; A 2 is a non-amide bond; A 3 is characterized by a backbone chain consisting of from 1 to 9 atoms, Y is a bond; C 1 is a derivative of Arg, Lys or Orn comprising a carboxylate moiety that is reduced, or displaced from the α-carbon by a moiety characterized by a backbone chain consisting of from 1 to 10 atoms; and C 2 is a non-cleavable bond; b) a linker moiety characterized by a backbone chain having a calculated length of between about 18 Å and about 42 Å; and c) an anion binding exosite associating moiety; said catalytic site-directed moiety being bound to said linker moiety and said linker moiety being bound to said anion binding exosite associating moiety; wherein said inhibitor is capable of simultaneously binding to the catalytic site and the anion binding exosite of thrombin.
Claim 2
Dependent Claim
223 words
A thrombin inhibitor consisting of: a) a catalystic site-directed moiety that binds to and inhibits the active site of thrombin; wherein said catalytic site-directed moiety is selected from serine proteinase inhibitors, heterocyclic protease inhibitors, thrombin-specific inhibitors, transition state analogues, benzamidine, DAPA, NAPAP, argipidine, or moieties of the formulae: X--A.sub.1 --A.sub.2 --A.sub.3 --Y or X--C.sub.1 --C.sub.2 --A.sub.3 --Y, wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 35 atoms; A 1 is Arg, Lys or Orn; A 2 is a non-amide bond; A 3 is characterized by a backbone chain consisting of from 1 to 9 atoms, Y is a bond; C 1 is a derivative of Arg, Lys or Orn comprising a carboxylate moiety that is reduced, or displaced from the α-carbon by a moiety characterized by a backbone chain consisting of from 1 to 10 atoms; and C 2 is a non-cleavable bond; b) a linker moiety characterized by a backbone chain having a calculated length of between about 18 Å and about 42 Å; and c) an anion binding exosite associating moiety; said catalytic site-directed moiety being bound to said linker moiety and said linker moiety being bound to said anion binding exosite associating moiety; wherein said inhibitor is capable of simultaneously binding to the catalytic site and the anion binding exosite of thrombin.
Claim 3
Dependent Claim
162 words
The thrombin inhibitor according to claim 1, wherein said anion binding exosite moiety consists of the formula: W--B.sub.1 --B.sub.2 --B.sub.3 --B.sub.4 --B.sub.5 --B.sub.6 --B.sub.7 --B.sub.8 --Z; wherein W is a bond; B 1 is an anionic amino acid; B 2 is any amino acid; B 3 is Ile, Val, Leu, Nle or Phe; B 4 is Pro, Hyp, 3,4-dehydroPro, thiazolidine-4-carboxylate, Sar, any N-methyl amino acid or D-Ala; B is an anionic amino acid; B 6 is an anionic amino acid; B 7 is a lipophilic amino acid selected from the group consisting Tyr, Trp, Phe, Leu, Nle, Ile, Val, Cha, Pro, or a dipeptide consisting of one of these lipophilic amino acids and any amino acid; B 8 is a bond or a peptide containing form one to five residues of any amino acid; and Z is a carboxy terminal residue selected from OH, C 1 --C 6 alkoxy, amino, mono- or di-(C 1 --C 4 ) alkyl substituted amino or benzylamino.
Claim 4
Dependent Claim
53 words
The thrombin inhibitor according to claim 2, wherein B 1 is Glu; B is Glu; B 2 is Ile; B 3 is Pro; B 5 is Glu; B 6 is Glu; B 7 is Tyr-Leu, Tyr(SO 3 H)-Leu, Tyr(OSO 3 H)-Leu or (3-, 5-diiodoTyr)-Leu; B 8 is a bond; and Z is OH.
Claim 5
Dependent Claim
32 words
The thrombin inhibitor according to claim 1, wherein said backbone chain of said linker moiety consists of any combination of atoms selected from the group consisting of carbon, nitrogen, sulfur and oxygen.
Claim 6
Dependent Claim
16 words
The thrombin inhibitor according to claim 4, wherein said linker comprises the amino acid sequence: Gly-Gly-Gly-Asn-Gly-Asp-Phe.
Claim 7
Dependent Claim
21 words
The thrombin inhibitor according to claim 1, wherein said catalytic site-directed moiety binds reversibly to and is slowly cleaved by thrombin.
Claim 8
Dependent Claim
21 words
The thrombin inhibitor according to claim 1, wherein said catalytic site-directed moiety binds reversibly to and cannot be cleaved by thrombin.
Claim 9
Dependent Claim
16 words
The thrombin inhibitor according to claim 1, wherein said catalytic site-directed moiety binds irreversibly to thrombin.
Claim 10
Dependent Claim
23 words
The thrombin inhibitor according to claim 1, wherein X is D-Phe-Pro; A 1 is Arg; and A 3 is D-Pro, Pro, or Sar.
Claim 11
Dependent Claim
21 words
The thrombin inhibitor according to claim 9, wherein said thrombin inhibitor is selected from the group consisting of Hirulog-8 and Hirulog-12.
Claim 12
Dependent Claim
20 words
The thrombin inhibitor according to claim 1, wherein X is N-acetyl-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val; A 1 is Arg; and A 3 is Pro.
Claim 13
Dependent Claim
16 words
The thrombin inhibitor according to claim 1, selected from the group consisting of Hirulog-18a and Hirulog-18b.
Claim 14
Dependent Claim
33 words
A pharmaceutically acceptable composition comprising an amount of a thrombin inhibitor according to claim 1, effective for inhibiting a thrombin-mediated function in a patient or in extracorporeal blood and a pharmaceutically acceptable carrier.
Claim 15
Dependent Claim
26 words
The pharmaceutically acceptable composition according to claim 13, wherein said pharmaceutically effective amount is between about 1 μg/kg body weight/day to about 5 mg/kg body weight/day.
Claim 16
Dependent Claim
26 words
The pharmaceutically acceptable composition according to claim 14, wherein said pharmaceutically effective amount is between about 10 μg/kg body weight/day to about 500 μg/kg body weight/day.
Claim 17
Dependent Claim
33 words
A composition for coating the surface of an invasive device to be inserted into a patient, wherein said composition comprises a suitable buffer and at least one thrombin inhibitor according to claim 1.
Claim 18
Dependent Claim
32 words
A pharmaceutically acceptable combination for treating or preventing thrombotic disease in a patient comprising: a) a thrombin inhibitor according to claim 1; b) a thrombolytic agent; and c) a pharmaceutically acceptable carrier.
Claim 19
Dependent Claim
20 words
The pharmaceutically acceptable combination according to claim 17, wherein said thrombin inhibitor is Hirulog-8 and said thrombolytic agent is tPA.
Claim 20
Dependent Claim
52 words
The combination according to claim 17, wherein the daily dosage of said thrombin inhibitor is between about 1 μg/kg body weight and about 5 mg/kg body weight and wherein the daily dosage of said thrombolytic agent is between about 10% and about 80% of the conventional dosage range of said thrombolytic agent.
Claim 21
Dependent Claim
52 words
The combination according to claim 19, wherein the daily dosage of said thrombin inhibitor is between about 10 μg/kg body weight and about 500 μg/kg body weight and wherein the daily dosage of said thrombolytic agent is between about 10% and about 70% of the conventional dosage range of said thrombolytic agent.
Claim 22
Dependent Claim
75 words
The thrombin inhibitor according to claim 2, wherein said linker moiety is characterized by a backbone chain having a calculated length of between about 18 Å and 36 Å and is selected from the group consisting of an acyl group of from about 17 to 35 carbon atoms, an alkyl group of from about 17 to 35 backbone bonds, a peptide containing from about 6 to 12 residues of any amino acid and combinations thereof.
Claim 23
Dependent Claim
83 words
The thrombin inhibitor according to claim 3, wherein: B 7 is Tyr(SO 3 H)-Leu or Tyr(OSO 3 H)-Leu; the linker is a peptide of from about 8 to 10 amino acids, the amino acid of said linker which is closest to the anion binding exosite moiety being Phe; and the catalytic site-directed moiety consists of the formula: X--Arg--R, wherein X is selected from the group consisting of D-Phe-Pro and tosyl-Gly; and R is selected from group consisting of Pro, Sar and N-methyl Ala.
Claim 24
Dependent Claim
13 words
The thrombin inhibitor according to claim 11, wherein said thrombin inhibitor is Hirulog-33.
Claim 25
Dependent Claim
17 words
The composition according to any one of claims 13-15 or 16, wherein said thrombin inhibitor is Hirulog-8.
Claim 26
Dependent Claim
18 words
The combination according to any one of claims 17, 19 or 20, wherein said thrombin inhibitor is Hirulog-8.
Claim 27
Dependent Claim
43 words
A method for decreasing the dose of a thrombolytic agent effective to establish reperfusion or to delay reocclusion in a patient, said method comprising the step of administering said thrombolytic agent to said patient as part of a combination according to claim 18.
Claim 28
Dependent Claim
68 words
A method for decreasing the reperfusion time and increasing the reocclusion time in a patient treated with a thrombolytic agent, said method comprising the step of administering to said patient a composition according to claim 13, wherein said composition is administered to said patient during the time period ranging from about 5 hours prior to about 5 hours following the treatment of said patient with said thrombolytic agent.
Claim 29
Dependent Claim
38 words
The method according to claim 27, wherein said composition is administered to said patient during the time period ranging from about 2 hours prior to about 2 hours following said treatment of said patient with said thrombolytic agent.
Claim 30
Dependent Claim
34 words
A method of inhibiting thrombin's catalytic and receptor-mediated functions in a patient or in extracorporeal blood comprising the step of treating said patient or said extracorporeal blood with a composition according to claim 13.
Claim 31
Dependent Claim
21 words
The method according to claim 29, wherein said method is used for treating or preventing a thrombotic disease in a patient.
Claim 32
Dependent Claim
20 words
The method according to claim 29, wherein said method is used for treating or preventing thrombin-induced inflammation in a patient.
Claim 33
Dependent Claim
30 words
The method according to claim 31, wherein said inflammation is caused by a disease selected from the group consisting of adult respiratory distress syndrome, septic shock, septicemia and reperfusion damage.
Claim 34
Dependent Claim
22 words
The method according to claim 29, wherein said method is used to inhibit thrombus accretion in a patient caused by clot-bound thrombin.
Claim 35
Dependent Claim
18 words
The method according to claim 29, wherein said method is used for inhibiting platelet-dependent thrombosis in a patient.
Claim 36
Dependent Claim
21 words
The method according to claim 29, wherein said method is used for treating or preventing disseminated intravascular coagulation in a patient.
Claim 37
Independent Claim
17 words
The method according to any one of claims 26-28 or 29-35, wherein said patient is a human.
Claim 38
Independent Claim
23 words
The method according to any one of claims 26-28 or 29-35, wherein said thrombin inhibitor employed in said composition or combination is Hirulog-8.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1996-03-22 | 1996-09-21 | 1997-03-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-03-22 | 2000-09-21 | 2001-03-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-03-22 | 2004-09-21 | 2005-03-23 | $7700.00 | Window Closed / Lapsed |