Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-04-20
2000-10-24
Davenport, Avis M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, A61K 3800, A61K 3802
Patent
active
061367826
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to antithrombotic agents and uses thereof. Specifically, the invention relates to compounds that bind to platelets, specifically compounds that bind to the platelet receptor molecule GPIIb/IIIa. Such compounds include peptides and cyclic peptides that bind to platelets and inhibit their aggregation. In particular, the platelet-specific antithrombotic agents of the invention are covalently linked to a polyvalent linker moiety, so that the polyvalent linker moiety is covalently linked to a multiplicity of the platelet-specific moieties, particularly peptides and cyclic peptides, thereby providing the multimeric polyvalent antithrombotic agents of the invention. The invention also provides methods for using such compounds to prevent the formation of thrombi at sites in a mammalian body.
2. Description of the Prior Art
Thrombosis and thromboembolism, in particular deep vein thrombosis (DVT) and pulmonary embolism (PE), are common clinical conditions that are associated with significant morbidity and mortality. It has been estimated that in the U.S. approximately 5 million patients experience one or more episodes of DVT per year and that over 500,000 cases of pulmonary embolism occur, resulting in 100,000 deaths (J. Seabold, Society of Nuclear Medicine Annual Meeting 1990).
In addition, myocardial infarction (heart attack) is usually caused by thrombosis in a coronary artery, often at the site of an atherosclerotic plaque. Conventional therapies for heart attack involve removing such thrombi, either surgically by angioplasty and/or by adminstration of thrombolytic drugs, such as recombinant tissue plasminogen activator or streptokinase. Following such therapy, however, re-stenosis or even re-occlusion of the affected coronary artery frequently occurs due to formation of another thrombus at the site of the original thrombus. Preventing such re-occurrence of coronary artery thrombi is thus an important goal of all post-infarct therapy.
The physiological processes involved in the formation of thrombi are initiated by the accumulation of platelets at sites of damage or insult to the endothelial cell wall of a blood vessel, such as an atheroschlerotic plaque. Platelets normally accumulate at such sites after stimulation by local mediators signalling the injury. Subsequently, such platelets become aggregated at such sites by binding serum fibrinogen via GPIIb/IIIa receptors expressed on the platelet surface. It is with the binding of fibrinogen that such an aggregation of platelets becomes a thrombus.
The amino acid sequence of the fibrinogen molecule recognized by GPIIb/IIIa receptors is the sequence -Arg-Gly-Asp- (RGD), which sequence is present four times in each fibrinogen molecule. Platelet aggregation can be inhibited using fibrinogen antagonists that bind to the GPIIb/IIIa receptors. Thus, compounds that are fibrinogen antagonists and bind to GPIIb/IIIa are useful in preventing thrombosis, particularly in post-angioplasty or post-thrombolytic treatment regimes.
Peptides having the ability to bind to platelets and inhibit their aggregation are known in the prior art.
Ruoslahti & Pierschbacher, U.S. Pat. No. 4,578,079 describe peptides of sequence X-Arg-Gly-Asp-R-Y, wherein X and Y are either H or an amino acid, and R is Thr or Cys, the peptides being capable of binding to platelets.
Ruoslahti & Pierschbacher, U.S. Pat. No. 4,792,525 describe peptides of sequence Arg-Gly-Asp-X, wherein X is Ser, Thr or Cys, the peptides being capable of binding to platelets.
Pierschbacher er al., 1989, International Application No. WO089/05150 disclose conformationally-restricted RGD-containing peptides for inhibiting cell attachment to a substratum.
Hawiger et al., 1989, International Application No. WO089/10135 relates to peptides comprising sequences for two binding sites of a protein.
Nutt et al., 1990, European Patent Application, Publication No. 0410537A1 disclose cyclic RGD peptides that are fibrinogen receptor antagonists.
Nutt et al., 1990, Eu
REFERENCES:
patent: 4614517 (1986-09-01), Ruoslahti et al.
patent: 5338725 (1994-08-01), Ojima et al.
Cheronis, "Bissuccinimidoalkane Peptide Dimers" (1992) J. Med. Chem., v. 35, No. 9, pp. 1563-1572.
Pierschbacher et al. "Influence Stereochemistry RGD" (1987) J. Biol. Chem., v. 262, No. 36, pp. 17294-17298.
Andrieux et al., "Platelet Fibrinogen Meleator" (1987) Caplus #1988:490296.
S.Bajusz, "Significance D-Amino Acids in Peptides" (1979) Pharmazie, H. 5/6 .
Dean Richard T.
Lister-James John
Davenport Avis M.
Diatide, Inc.
McDoniels Patricia A.
Noonan Kevin
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