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Claims for Patent: 5,196,404

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Claims for Patent: 5,196,404

Title: Inhibitors of thrombin
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 .ANG. 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.
Inventor(s): Maraganore; John M. (Concord, MA), Fenton, II; John W. (Malden Bridge, NY), Kline; Toni (New York, NY)
Assignee: Biogen, Inc. (Cambridge, MA) Health Research, Inc. (Albany, NY)
Application Number:07/549,388
Patent Claims: 1. 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:

wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 35 atoms; A.sub.1 is Arg, Lys or Orn; A.sub.2 is a non-amide bond; A.sub.3 is characterized by a backbone chain consisting of from 1 to 9 atoms, Y is a bond; C.sub.1 is a derivative of Arg, Lys or Orn comprising a carboxylate moiety that is reduced, or displaced from the .alpha.-carbon by a moiety characterized by a backbone chain consisting of from 1 to 10 atoms; and C.sub.2 is a non-cleavable bond;

b) a linker moiety characterized by a backbone chain having a calculated length of between about 18 .ANG. and about 42 .ANG.; 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.

2. The thrombin inhibitor according to claim 1, wherein said anion binding exosite moiety consists of the formula:

wherein W is a bond; B.sub.1 is an anionic amino acid; B.sub.2 is any amino acid; B.sub.3 is Ile, Val, Leu, Nle or Phe; B.sub.4 is Pro, Hyp, 3,4-dehydroPro, thiazolidine-4-carboxylate, Sar, any N-methyl amino acid or D-Ala; B.sub.is an anionic amino acid; B.sub.6 is an anionic amino acid; B.sub.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.sub.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.sub.1 --C.sub.6 alkoxy, amino, mono- or di-(C.sub.1 --C.sub.4) alkyl substituted amino or benzylamino.

3. The thrombin inhibitor according to claim 2, wherein B.sub.1 is Glu; B.sub.is Glu; B.sub.2 is Ile; B.sub.3 is Pro; B.sub.5 is Glu; B.sub.6 is Glu; B.sub.7 is Tyr-Leu, Tyr(SO.sub.3 H)-Leu, Tyr(OSO.sub.3 H)-Leu or (3-, 5-diiodoTyr)-Leu; B.sub.8 is a bond; and Z is OH.

4. 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.

5. The thrombin inhibitor according to claim 4, wherein said linker comprises the amino acid sequence: Gly-Gly-Gly-Asn-Gly-Asp-Phe.

6. The thrombin inhibitor according to claim 1, wherein said catalytic site-directed moiety binds reversibly to and is slowly cleaved by thrombin.

7. The thrombin inhibitor according to claim 1, wherein said catalytic site-directed moiety binds reversibly to and cannot be cleaved by thrombin.

8. The thrombin inhibitor according to claim 1, wherein said catalytic site-directed moiety binds irreversibly to thrombin.

9. The thrombin inhibitor according to claim 1, wherein X is D-Phe-Pro; A.sub.1 is Arg; and A.sub.3 is D-Pro, Pro, or Sar.

10. The thrombin inhibitor according to claim 9, wherein said thrombin inhibitor is selected from the group consisting of Hirulog-8 and Hirulog-12.

11. The thrombin inhibitor according to claim 1, wherein X is N-acetyl-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val; A.sub.1 is Arg; and A.sub.3 is Pro.

12. The thrombin inhibitor according to claim 1, selected from the group consisting of Hirulog-18a and Hirulog-18b.

13. 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.

14. The pharmaceutically acceptable composition according to claim 13, wherein said pharmaceutically effective amount is between about 1 .mu.g/kg body weight/day to about 5 mg/kg body weight/day.

15. The pharmaceutically acceptable composition according to claim 14, wherein said pharmaceutically effective amount is between about 10 .mu.g/kg body weight/day to about 500 .mu.g/kg body weight/day.

16. 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.

17. 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.

18. The pharmaceutically acceptable combination according to claim 17, wherein said thrombin inhibitor is Hirulog-8 and said thrombolytic agent is tPA.

19. The combination according to claim 17, wherein the daily dosage of said thrombin inhibitor is between about 1 .mu.g/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.

20. The combination according to claim 19, wherein the daily dosage of said thrombin inhibitor is between about 10 .mu.g/kg body weight and about 500 .mu.g/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.

21. 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 .ANG. and 36 .ANG. 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.

22. The thrombin inhibitor according to claim 3, wherein:

B.sub.7 is Tyr(SO.sub.3 H)-Leu or Tyr(OSO.sub.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:

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.

23. The thrombin inhibitor according to claim 11, wherein said thrombin inhibitor is Hirulog-33.

24. The composition according to any one of claims 13-15 or 16, wherein said thrombin inhibitor is Hirulog-8.

25. The combination according to any one of claims 17, 19 or 20, wherein said thrombin inhibitor is Hirulog-8.

26. 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.

27. 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.

28. 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.

29. 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.

30. The method according to claim 29, wherein said method is used for treating or preventing a thrombotic disease in a patient.

31. The method according to claim 29, wherein said method is used for treating or preventing thrombin-induced inflammation in a patient.

32. 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.

33. The method according to claim 29, wherein said method is used to inhibit thrombus accretion in a patient caused by clot-bound thrombin.

34. The method according to claim 29, wherein said method is used for inhibiting platelet-dependent thrombosis in a patient.

35. The method according to claim 29, wherein said method is used for treating or preventing disseminated intravascular coagulation in a patient.

36. The method according to any one of claims 26-28 or 29-35, wherein said patient is a human.

37. 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.
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