.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 5,433,940

« Back to Dashboard

Details for Patent: 5,433,940

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 (Cambridge, MA)
Assignee: Biogen, Inc. (Cambridge, MA)
Filing Date:Feb 10, 1992
Application Number:07/834,259
Claims:1. A thrombin inhibitor consisting of:

a) a catalytic site-directed moiety that binds to and inhibits the active site of thrombin wherein said catalytic site-directed moiety is selected from general 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.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 structure characterized by a backbone chain 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 18.ANG. and 42.ANG.; and

c) an anion binding exosite associating moiety;

said catalytic site-directed moiety being bound to said linked moiety and said linker moiety being bound to said anion binding exosite moiety, wherein said inhibitor is labeled with a radioisotope and 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.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 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 from 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.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.

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 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 composition for imaging of a fibrin or a platelet thrombus in a patient, said composition comprising a pharmaceutically acceptable buffer and a thrombin inhibitor according to any one of claims 1 or 2-12.

14. A method for imaging a fibrin or a platelet thrombus in a patient comprising the steps of:

a) administering to said patient a composition according to claim 13; and

b) using detecting means to observe the thrombin inhibitor present in said composition.

15. The thrombin inhibitor according to any one of claims 1 to 12, wherein said radioisotope is selected from the group consisting of .sup.123 I, .sup.125 I and .sup.111 n.

16. A composition for imaging of a fibrin or a platelet thrombus in a patient, said composition comprising a pharmaceutically acceptable buffer and a thrombin inhibitor according to claim 15.

17. The method according to claim 14 wherein said patient is a human.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc