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Details for Patent: 5,240,913

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Details for Patent: 5,240,913

Title: Inhibitors of thrombin
Abstract:This invention relates to novel biologically active molecules which bind to and inhibit thrombin. These molecules comprise a catalytic site directed moiety (CSDM) of the formula ##STR1## wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 100 atoms; R.sub.1 is selected from the group consisting of unsubstituted, monosubstituted, di-substituted and tri-substituted saturated ring structures; R.sub.2 is a bond or is characterized by a backbone chain consisting of from 1 to 5 atoms; R.sub.3 is a bond or is characterized by a backbone chain consisting of from 1 to 3 atoms; R.sub.4 is any amino acid; R.sub.5 is any L-amino acid which comprises a guanidinium- or amino-containing side chain group; R.sub.6 is a non-amide bond; and Y is characterized by a backbone chain consisting of from 1 to 9 atoms; or the formula: ##STR2## wherein R'.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted ring structures; R'.sub.4 is any amino acid comprising a side chain group characterized by the capacity to accept a hydrogen bond at a pH of between about 5.5 and 9.5; and X, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and Y are defined as above. Preferred thrombin inhibitors are further characterized by a anion binding exosite associating domain (ABEAM) and a linker portion of between 18 .ANG. and 42 .ANG. in length which connects the Y to the ABEAM. This invention also relates to compositions, combinations and methods which employ these molecules for therapeutic, prophylactic and diagnostic purposes.
Inventor(s): Maraganore; John M. (Tewksbury, MA), Jablonski; Jo-Ann M. (Middleborough, MA), Bourdon; Paul R. (Somerville, MA)
Assignee: Biogen, Inc. (Cambridge, MA)
Filing Date:Feb 08, 1991
Application Number:07/652,929
Claims:1. A thrombin inhibitor consisting of:

a) a catalytic site-directed moiety consisting of the formula: ##STR10## wherein X is hydrogen or is characterized by a backbone chain consisting of from 1 to 100 atoms; R.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted saturated homocyclic or heterocyclic ring structures; R.sub.2 is a bond or is characterized by a backbone chain consisting of from 1 to 5 atoms; R.sub.3 is a bond or is characterized by a backbone chain consisting of from 1 to 3 atoms; R.sub.4 is any amino acid; R.sub.5 is any L-amino acid which comprises a guanidinium- or amino-containing side chain group; R.sub.6 is a non-amide bond; and Y is characterized by a backbone chain consisting of from 1 to 9 atoms;

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 X is H.sub.2 N; R.sub.1 is selected from the group consisting of unsubstituted, mono-substituted, di-substituted and tri-substituted cyclohexane; R.sub.2 is CH.sub.2 --CH; and R.sub.3 is C.dbd.O.

3. The thrombin inhibitor according to claim 2, wherein the catalytic site-directed moiety has the amino acid sequence: D-Cha-Pro-Arg-Pro.

4. The thrombin inhibitor according to claim 42, 43 or 3, wherein said anion binding exosite associating 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.5 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 of Tyr, Trp, Phe, Leu, Nle, Ile, Val, Cha, Pro, or a dipeptide consisting of one of said lipophilic amino acids and any amino acid; B.sub.8 is a bond or a peptide containing from one to five residues of any amino acid; and Z is OH or is characterized by a backbone chain consisting of from 1 to 6 atoms.

5. The thrombin inhibitor according to claim 4, wherein B.sub.1 is Glu; B.sub.2 is Glu; B.sub.3 is Ile; B.sub.4 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.

6. The thrombin inhibitor according to claim 1, 2 or 3, 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.

7. The thrombin inhibitor according to claim 6, wherein said linker comprises the amino acid sequence; Gly-Gly-Gly-Asn-Gly-Asp-Phe.

8. The thrombin inhibitor D-Cha-Hirulog-8.

9. 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.

10. The pharmaceutically acceptable composition according to claim 9, wherein said amount of thrombin inhibitor is between about 0.5 nmoles/kg body weight and about 2.5 .mu.moles/kg body weight.

11. The pharmaceutically acceptable composition according to claim 10, wherein said amount of thrombin inhibitor is between about 5 nmoles/kg body weight and about 250 nmoles/kg body weight.

12. 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.

13. 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.

14. The combination according to claim 13, wherein said thrombin inhibitor is D-Cha-Hirulog-8 and said thrombolytic agent is tPA.

15. The combination according to claim 14, wherein the daily dosage of said thrombin inhibitor is between about 0.5 nmoles/kg body weight and about 2.5 .mu.moles/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.

16. The combination according to claim 15, wherein the daily dosage of said thrombin inhibitor is between about 5 nmoles/kg body weight and about 250 nmoles/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.

17. 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 13.

18. 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 9, 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.

19. The method according to claim 18, 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.

20. The composition according to claim 9, 10, 11 or 12, wherein said thrombin inhibitor is D-Cha-Hirulog-8.

21. The combination according to claim 13, 14, 15 or 16, wherein said thrombin inhibitor is D-Cha-Hirulog-8.

22. A method for inhibiting the catalytic and receptor-mediated functions of thrombin in a patient or in extracorporeal blood comprising the step of treating said patient or said extracorporeal blood with a composition according to claim 9.

23. The method according to claim 22, wherein said method is used to treat or prevent a thrombotic disease in a patient.

24. The method according to claim 22, wherein said method is used to treat or prevent thrombin-induced inflammation in a patient.

25. The method according to claim 24, wherein said inflammation is caused by a disease selected from the group consisting of adult respiratory distress syndrome, septic shock, septicemia and reperfusion damage.

26. The method according to claim 22, wherein said method is used to inhibit thrombus accretion in a patient caused by clot-bound thromin.

27. The method according to claim 22, wherein said method is used to inhibit platelet-dependent thrombosis in a patient.

28. The method according to claim 22, wherein said method is used to treat or prevent disseminated intravascular coagulation in a patient.

29. The method according to claim 17, 18, 19, 22, 23, 24, 25, 26, 27 or 28, wherein said patient is a human.

30. The method according to claim 17, 18, 19, 22, 23, 24, 25, 26, 27 or 28, wherein said thrombin inhibitor employed in said composition or combination is D-Cha-Hirulog-8.
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