Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving blood clotting factor
Patent
1997-10-08
1998-12-15
Leary, Louise N.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving blood clotting factor
435 725, 435 4, 435 2, 436520, 436521, 436522, 436 15, 436 63, 436 68, 436 69, 436 74, 530300, 530380, 530381, 530384, 530385, C12Q 156, C12Q 100, G01N 3353, A61K 3800
Patent
active
058495100
ABSTRACT:
The invention provides compounds which specifically inhibit factor Xa activity. The compounds consist of the structure X.sub.1 -YIR-X.sub.2, wherein X.sub.1 is H, acyl, alkyl, acylalkyl, arylalkyl or one or more amino acids, and X.sub.2 is a modified C-terminal group, one or more carboxy-protecting groups or one or more amino acids or other substituent, and Y, I and R are tyrosine, isoleucine and arginine, respectively, or peptidomimetic or organic structures that possess the same functional activity as Y, I and R, respectively. In addition, the present invention provides a compound having the structure A1-A2-(A3).sub.m --B, where m is 0 or 1. A compound of the invention can be linear or cyclic and can be about 2 and 43 residues in length. A compound of the invention is characterized, in part, in that it exhibits a specific inhibition of factor Xa activity with a K.sub.i of .ltoreq.100 .mu.M, preferably .ltoreq.2 nM, and does not substantially inhibit the activity of other proteases involved in the coagulation cascade. The invention further provides methods of specifically inhibiting the activity of factor Xa and of inhibiting blood clotting in vitro and in an individual and methods of detecting factor Xa levels or activity.
REFERENCES:
patent: 4428874 (1984-01-01), Svendsen et al.
patent: 4605614 (1986-08-01), Nagasawa et al.
patent: 4772553 (1988-09-01), Fujii et al.
patent: 5023236 (1991-06-01), Edgington et al.
patent: 5189019 (1993-02-01), Palladino et al.
patent: 5239058 (1993-08-01), Vlasuk et al.
patent: 5240913 (1993-08-01), Maraganore et al.
patent: 5328997 (1994-07-01), Vlasuk et al.
patent: 5439888 (1995-08-01), Shuman et al.
Claeson and Aurell, "Small Synthetic Peptides with Affinity for Proteases in Coagulation and Fibrinolysis," Ann. N.Y. Acad. Sci. (USA) 370:798-811 (1981).
Jorgenson et al., Angiotensin II Analogs. 6..sup.1 Stereochemical Factors in the 5 Position Influencing Pressor Activity. 1, J. Med. Chem. 14:899-903 (1971).
Maule et al., "RYIRFamide: a Turbellarian FMRFamide-related peptide (FaRI)," Regulatory Peptides 50:37-43 (1994).
Messmore et al., "Coagulant Enzymes and Synthetic Inhibitors," Thromb. Haemostasis 42:952 (1979).
Ponsati et al., "A Synthetic Strategy for Simultaneous Purification-Conjugation of Antigenic Peptides," Analytical Biochemistry 181:889-395 (1989).
Shaw, "Synthetic Irreversible of Coagulation Enzymes," Folia Haematol. 109:33-42 (1982).
Choay, et al., "Structure-Activity Relationship in Heparin: A Synthetic Pentasaccharide with High Affinity for Antithrombin III and Eliciting High Anti-Factor Xa Activity," Bioch. Biophys. Res. Com. 116:492-499 (1983).
de Feyer, et al., "Acute Coronary Artery Occlusion During and After Percutaneous Transluminal Coronary Angioplasty," Circulation 83:927-936 (1991).
Detre, et al., "Incidence and Consequences of Periprocedural Occlusion," Circulation 82:739-750 (1991).
Dunwiddle, et al., "Antistasin, a Leech-derived Inhibitor of Factor Xa," J. Biol. Chem. 264:16694-16696 (1989).
Harenberg, "Relation of Antifactor Xa Activity of Heparins and Antithrombotic Efficacy," Haemostasis 18:16-19 (1988).
Hauptmann, et al., "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors," Thromb. Haemost. 63:220-223 (1990).
Hogg, et al., "Fibrin Monomer Protects Thrombin from Inactivation by Heparin-Antithrombin III: Implications for Heparin Efficacy," PNAS 86:3619-3623 (1989).
Lincoff, et al., "Abrupt Vessel Closure Complicating Coronary Angioplasty: Clinical, Angiographic and Therapeutic Profile," J. Am. Coll. Cardiol. 19:926-935 (1992).
Mann and Lorand, "Introduction: Blood Coagulation," Methods in Enzymology 222:1-10 (1993).
Maraganore, "Design and Characterization of Hirulogs: A Novel Class of Bivalent Peptide Inhibitors of Thrombin," Biochemistry 29:7095-7101 (1990).
Meuleman, "Orgaran (Org 10172): Its Pharmacological Profile in Experimental Models," Haemostasis 22:58-65 (1992).
Nutt, et al., "The Amino Acid Sequence of Antistasin," J. Biol. Chem. 263:10162-10167 (1988).
Ofosu, et al., "An Approach to Assigning In Vitro Potency to Unfractioned and Low Molecular Weight Heparins Based on the Inhibition of Prothrombin Activation and Catalysis of Thrombin Inhibition," Thromb. Haemost. 60:193-198 (1988).
Schaffer, et al., "Antithrombotic Efficacy of Recombinant Tick Anticoagulant Peptide, A Potent Inhibitor of Coagulation Factor Xa in a Primate Model of Arterial Thrombosis," Circulation 84:1741-1747 (1991).
Swayze, et al., "Deep Venous Thrombosis in Total Hip Arthroplasty," Orthop. Clin. North. Am., 23:359-364 (1992).
Teitel and Rosenberg, "Protection of Factor Xa from Neutralization by the Heparin-Antithrombin Complex," J. Clin. Invest. 71:1383-1391 (1983).
Tidwell, et al., "Strategies for Anticoagulation with Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors," Thromb. Res. 19:339-349 (1980).
Topol, et al., "Use of a Direct Antithrombin, Hirulog, in Place of Heparin During Coronary Angioplasty," Circulation 87:1622-1629 (1993).
Turpie, et al., "A Randomized Controlled Trial of a Low-Molecular Weight Heparin (Enoxaparin) to Prevent Deep-Vein Thrombosis in Patients Undergoing Elective Hip Surgery," New Eng. J. Med. 315:925-929 (1986).
Vlasuk, "Comparison of the In Vivo Anticoagulant Properties of Standard Heparin and the Highly Selective Factor Xa Inhibitors Antistasin and Tick Anticoagulant Peptide (TAP) in a Rabbit Model of Venous Thrombosis," Thromb. Haemost. 65:257-262 (1991).
Waxman, et al., "Tick Anticoagulant Peptide (TAP) Is a Novel Inhbitor of Blood Coagulation Factor Xa," Science 248:593-596 (1990).
Wessler "Mini-Dose Heparin," Thrombos. Diathes. Hemorrh. 34:718-726 (1978).
Yin "Heparin-Accelerated Inhibition of Activated Factor Xa by its Natural Plasma Inhibitor," Bioch. Biophys. Acta. 201:387-390 (1970).
Al-Obeidi Fahad
Lebl Michal
Ostrem James A.
Safar Pavel
Stierandova Alena
Leary Louise N.
Selectide Corporation
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