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Claims for Patent: 5,807,825

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Claims for Patent: 5,807,825

Title: Platelet aggregation inhibitors
Abstract:An assay for screening snake venom for the presence or absence of platelet aggregation inhibitors (PAIs) based on specific receptor binding is described. Using this assay, the identification and characterization of PAIs in a wide range of snake venom samples was accomplished. The isolated and purified PAI from several of these active snake venoms is described and characterized. In addition, PAIs lacking the Arg-Gly-Asp (RGD) adhesion sequence but containing K*-(G/Sar)-D wherein K* is a modified lysyl residue of the formula wherein each R.sup.1 is independently H, alkyl(1-6C) or at most one R.sup.1 is R.sup.2 --C.dbd.NR.sup.3 wherein R.sup.2 is H, alkyl(1-6C), phenyl or benzyl, or is NR.sup.4.sub.2 in which each R.sup.4 is independently H or alkyl(1-6C) and R is H, alkyl(1-6C), phenyl or benzyl, or R.sup.2 --C.dbd.NR.sup.3 is a radical selected from the group consisting of: ##STR1## where m is an integer of 2-3, and each R.sup.5 is independently H or alkyl(1-6C); and wherein one or two (CH.sub.2) may be replaced by O or S provided said O or S is not adjacent to another heteroatom are prepared and shown to specifically inhibit the binding of fibrinogen or von Willebrand Factor to GP IIb-IIIa.
Inventor(s): Scarborough; Robert M. (Belmont, CA), Wolf; David Lawrence (Palo Alto, CA), Charo; Israel F. (Lafayette, CA)
Assignee: COR Therapeutics, Inc. (South San Francisco, CA)
Application Number:08/482,278
Patent Claims: 1. A method of treating or preventing a platelet associated ischemic disorder in a patient comprising administering to said patient an effective amount of a platelet aggregation inhibitor of the formula: ##STR10## wherein Y.sub.1 -X.sub.1 is Mpr, n1 is 0, K* is Har, (Gly or Sar) is Gly, AA.sub.2 is Trp, n.sub.2 is 1, AA.sub.3 is Pro, n.sub.3 is 1, n.sub.4 is 0, X.sub.2 is Cys, Y.sub.2 is NH.sub.2, and ##STR11## represents a disulfide bond, or a physiologically acceptable basic or acid addition salt thereof.

2. A method according to claim 1, wherein said platelet aggregation inhibitor has the formula ##STR12##

3. A method according to claim 1, wherein said disorder is thrombus formation.

4. A method according to claim 1, wherein said disorder is acute myocardial infraction.

5. A method according to claim 1, wherein said disorder is thrombosis following angioplasty.

6. A method according to claim 1, wherein said disorder is unstable angina.

7. A method according to claim 1, wherein said disorder is atherosclerosis.

8. A method according to claim 1, wherein said disorder is characterized by transient ischemic attacks.

9. A method according to claim 1, wherein said disorder is peripheral vascular disease.

10. A method according to claim 1, wherein said disorder is restenosis following angioplasty.

11. A method according to claim 1, wherein said disorder is thrombosis following carotid endarterectomy.

12. A method according to claim 1, wherein said disorder is thrombosis following anastomosis of vascular grafts.

13. A method of preventing platelet loss during extracorporeal circulation of blood comprising contacting said blood with an effective amount of a platelet aggregation inhibitor of the formula: ##STR13## wherein Y.sub.1 -X.sub.1 is Mpr, n1 is 0, K* is Har, (Gly or Sar) is Gly, AA.sub.2 is Trp, n.sub.2 is 1, AA.sub.3 is Pro, n.sub.3 is 1, n.sub.4 is 0, X.sub.2 is Cys, Y.sub.2 is NH.sub.2, and ##STR14## represents a disulfide bond, or a physiologically acceptable basic or acid addition salt thereof.

14. A method according to claim 13, wherein said platelet aggregation inhibitor has the formula ##STR15##

15. A method of preventing platelet aggregation, embolization or consumption of extracorporeal circulation comprising administering an effective amount of a platelet aggregation inhibitor of the formula: ##STR16## wherein Y.sub.1 -X.sub.1 is Mpr, n1 is 0, K* is Har, (Gly or Sar) is Gly, AA.sub.2 is Trp, n.sub.2 is 1, AA.sub.3 is Pro, n.sub.3 is 1, n.sub.4 is 0, X.sub.2 is Cys, Y.sub.2 is NH.sub.2, and ##STR17## represents a disulfide bond, or a physiologically acceptable basic or acid addition salt thereof.

16. A method according to claim 15, wherein said platelet aggregation inhibitor formula ##STR18##

17. A method according to claim 15, wherein said platelet aggregation, embolization or consumption is due to extracorporeal circulation for renal dialysis.

18. A method according to claim 15, wherein said platelet aggregation, embolization or consumption is due to extracorporeal circulation for cardiopulmonary bypass.

19. A method according to claim 15, wherein said platelet aggregation, embolization or consumption is due to extracorporeal circulation for hemoperfusion.

20. A method according to claim 15, wherein said platelet aggregation, embolization or consumption is due to extracorporeal circulation for plasmapheresis.

21. A method according to claim 15, wherein said platelet aggregation, embolization or consumption is associated with an intravascular device.

22. A method according to claim 21, wherein said intravascular device is an intraaortic balloon pump.

23. A method according to claim 21, wherein said intravascular device is a ventricular assist device.

24. A method according to claim 21, wherein said intravascular device is an arterial catheter.
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