Claims
- 1. A method for treating a mammal susceptible to, suffering from, suspected of having or recovering from a disease impacted by tissue factor (TF), the method comprising administering to the mammal a therapeutically effective amount of at least one TF blocking compound to treat the disease.
- 2. The method of claim 1, wherein the disease is selected from the group consisting of a cardiovascular disease, a blood coagulation disorder, a cell proliferation disorder, post-operative complication, an immune disorder, atherosclerosis, inflammation or cancer.
- 3. A method of blocking or inhibiting tissue factor-dependent activation of factor X and/or factor IX, comprising contacting tissue factor with a TF blocking compound to thereby inhibit formation of a functional complex of factor X or factor IX with tissue factor or TF VIIA.
- 4. The method of claim 3 wherein the TF blocking compound binds to tissue factor to thereby inhibit formation of the functional complex.
- 5. The method of any one of claims 1-4 wherein the tissue factor blocking compound exhibits an IC50 of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.
- 6. The method of any one of claims 1-4 wherein the tissue factor blacking compound exhibits an IC50 of about 200 μM or less in a standard assay for measuring TF/VIIa-dependent factor IX activation.
- 7. The method of any one of claims 1-4 wherein the tissue factor compound comprises at least one phosphonate group.
- 8. The method of any one of claims 1-4 wherein the tissue factor compound comprises at least one bis-phosphonate group.
- 9. The method of claim 7 or 8 wherein the tissue factor compound further comprises an optionally substituted carbocyclic aryl group, or an optionally substituted heteroaryl group.
- 10. The method of claim 7 or 8 wherein the tissue factor compound further comprises an optionally substituted phenyl group.
- 11. The method of any one of claims 1-4 wherein the TF blocking compound is of the following Formula I:
- 12. The method of any one of claims 1-4 wherein the TF blocking compound is of the following Formula II:
- 13. A method for identifying a candidate TF blocking compound, the method comprising screening the compound in at least one primary screening assay using purified tissue factor; and selecting the TF blocking compound.
- 14. The method of claim 13 further comprising screening the candidate TF blocking compound in at least one secondary screening assay.
- 15. The method of claim 13 or 14 comprising screening the candidate TF blocking compound in a standard in vitro assay for measuring TF/VIIa-dependent factor X activation.
- 16. The method of claim 13 or 14 comprising screening the candidate TF blocking compound in a standard in vitro assay for measuring TF/VIIa dependent factor IX activation.
- 17. The method of claim 13 wherein the screening assay is a standard prothrombin time (PT) assay.
- 18. The method of any of claims 13-17 wherein the purified tissue factor is lipidated recombinant human tissue factor.
- 19. A tissue factor (TF) blocking compound exhibiting an IC50 of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.
- 20. The compound of claim 19 further exhibiting equivalent or greater than about 70% inhibition in the assay.
- 21. The compound of claim 19 further exhibiting an IC50 of about 200 μM or less in a standard assay for measuring TF/VIIa-dependent factor IX activation.
- 22. The compound of claim 19 further exhibiting at least about a 5% to 20% increase in plasma clotting time relative to a control in a standard prothrombin time (PT) assay.
- 23. The compound of claim 19 further exhibiting at least 70% inhibition in the assay for measuring TF/VIIa-dependent factor X activation and at least of the following activities: 1) an IC50 of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor IX activation, and 2) at least about a 5% to 20% increase in plasma clotting time relative to a control in a standard prothrombin time (PT) assay.
- 24. The compound of claim 19 wherein the compound is represented by the following Formula I:
- 25. The compound of claim 19 wherein the compound is represented by the following Formula II:
- 26. The compound of claim 19 wherein the compound is represented by the following Formula III:
- 27. The compound of claim 19 wherein the compound is represented by the following Formula IIIa:
- 28. The compound of claim 19 wherein the compound is represented by the following Formula IV:
- 29. The compound of claim 19 wherein the compound is represented by the following Formula IVA:
- 30. A compound of any one of claims 24 through 27 wherein at least one R1 is hydroxy and m is 1 or 2.
- 31. A pharmaceutical composition comprising a compound of any one of claims 19 to 30 and a pharmaceutically acceptable carrier.
- 32. A method for treating a mammal suffering from or susceptible to a disease impacted by tissue factor, comprising administering to the mammal an effective amount of a compound or composition of any one of claims 19-31.
- 33. A method for treating a mammal suffering from or susceptible to a cardiovascular disease, a blood coagulation disorder, a cell proliferation disorder, post-operative complication, an immune disorder, atherosclerosis, inflammation, or cancer, comprising administering to the mammal an effective amount of a compound or composition of any one of claims 19-31.
- 34. A method of inhibiting blood coagulation in a mammal, comprising administering to the mammal an effective amount of a compound or composition of any one of claims 19 to 31.
- 35. The method of claim 34 wherein the mammal is suffering from, suspected of having, or recovering from a thrombosis.
- 36. The method of claim 34 wherein the mammal is suffering from, susceptible to, or recovering from restenosis associated with an invasive medical procedure.
- 37. The method of claim 34 wherein the invasive medical procedure is angioplasty, endarterectomy, deployment of a stent, use of catheter, graft implantation or use of an arteriovenous shunt.
- 38. The method of claim 34 wherein the mammal is suffering from, at risk of developing, or recovering from a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent.
- 39. The method of any one of claims 34-38 wherein at least one of an anti-platelet composition, thrombolytic composition or an anti-coagulant composition is administered in combination with a tissue factor blocking compound exhibiting an IC50 of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.
- 40. A method of treating or preventing a thromboembolic disorder in a mammal, comprising administering to the mammal an effective amount of the TF blocking compound of any one of claims 19-31.
- 41. The method of claim 40 wherein the mammal is suffering from, at risk developing, or is recovering from a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent or an anti-platelet agent.
- 42. The method of claim 40 wherein at least one of an anti-platelet, thrombolytic, or an anti-coagulant composition is administered in combination with a tissue factor blocking compound exhibiting an IC50 of less than about 100 μM in a standard assay for measuring TF/VIIa-dependent factor X activation.
- 43. The method of any one of claims 32-42 wherein the mammal is a human.
- 44. A compound of the following Formula I:
- 45. A compound of claim 44 having the following Formula II:
- 46. A compound of claim 44 having the following Formula III:
- 47. A compound of claim 44 having the following Formula IIIa:
- 48. A compound of claim 44 having the following Formula IV:
- 49. A compound of claim 44 having the following Formula IVa:
- 50. A compound of any one of claims 44 through 46 wherein at least one R1 is hydroxy and m is 1 or 2.
- 51. A compound of claim 44, that is:
- 52. A method of inhibiting blood coagulation in a mammal, comprising administering to the mammal an effective amount of a compound of any one of claims 44 to 51.
- 53. The method of claim 52 wherein the mammal is suffering from or suspected of having a thrombosis.
- 54. The method of claim 52 wherein the mammal is suffering from or susceptible to restenosis associated with an invasive medical procedure.
- 55. The method of claim 54 wherein the invasive medical procedure is angioplasty, endarterectomy, deployment of a stent, use of catheter, graft implantation or use of an arteriovenous shunt.
- 56. The method of claim 52 wherein the mammal is suffering from or at risk of developing a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent.
- 57. The method of any one of claims 52 to 56 wherein an anti-platelet composition, a thrombolytic composition or an anti-coagulant composition is administered in combination with a compound of Formula I.
- 58. A method of treating or preventing a thromboembolic disorder in a mammal, comprising administering to the mammal an effective amount of a compound of any one of claims 44 to 51.
- 59. The method of claim 58 wherein the mammal is suffering from or at risk developing a thromboembolic condition associated with cardiovascular disease, an infectious disease, a neoplastic disease or use of a thrombolytic agent or an anti-platelet agent.
- 60. The method of claim 58 or 59 wherein an anti-platelet composition, a thrombolytic composition or an anti-coagulant composition is administered in combination with a compound of Formula I.
- 61. A method of treating a mammal suffering from or susceptible to atherosclerosis, comprising administering to the mammal an effective amount of a compound of any one of claims 44 to 51.
- 62. The method of any one of claims 52 to 61 wherein the mammal is a human.
- 63. A pharmaceutical composition comprising a compound of any one of claims 44 through 51 and a pharmaceutically acceptable carrier.
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application claims the benefit of U.S. Provisional Application No. 60/101,887 filed on Sep. 25, 1998, the disclosure of which is hereby incorporated by reference.