Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 15 to 23 amino acid residues in defined sequence
Patent
1994-10-24
1995-08-29
Warden, Jill
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
15 to 23 amino acid residues in defined sequence
C07K 700, C07K 708, A61K 3800
Patent
active
054461316
ABSTRACT:
This invention relates to novel, biologically active molecules which bind to and inhibit the thrombin receptor. These thrombin receptor antagonists are further characterized by their ability to inhibit thrombin-induced platelet aggregation and their inability to inhibit platelet aggregation induced by an internal peptide fragment of the platelet thrombin receptor. More specifically, the thrombin receptor antagonist of this invention comprises the formula: A.sub.1 -X-X-X-A.sub.2 -X-A.sub.3 -X-A.sub.4 -B-X-A.sub.5 -C-X-A.sub.6 ; wherein each of A.sub.1 and A.sub.6, either the same or different, are selected from the group consisting of a positively charged amino acid and an acyl or alkyl chain comprising from 1 to 10 backbone atoms and a positively charged side group; each of A.sub.2, A.sub.3, A.sub.4 and A.sub.5, is a positively charged amino acid, either the same or different; each X is any amino acid, either the same or different; B is an amino acid containing an aryl side chain; and C is a polar amino acid. This invention also relates to compositions and methods which employ these molecules for therapeutic and prophylactic purposes.
REFERENCES:
patent: 4859609 (1989-08-01), Dull et al.
patent: 5049132 (1991-09-01), Shaffer et al.
patent: 5071954 (1991-12-01), Felzer et al.
E. M. Ruda et al., "Identification of a Tripeptide Analogue (SC-40476) That Acts as a Selective Partial Agonist-Antagonist at the Human Platelet Thrombin Receptor", Ann. New York Acad. Sci., 485, pp. 439-442 (1986).
E. M. Ruda et al., "Thrombin Receptor Antagonists--Structure-Activity Relationships for the Platelet Thrombin Receptor and Effects on Prostacyclin Synthesis by Human Umbilican Vein Endothelial Cells", Biochem. Pharm., 39, pp. 373-381 (1990).
S. J. Friezner Degen et al., "Nucleotide Sequence of the Gene for Human Prothrombin", Biochemistry, 26, pp. 6165-6177 (1987).
G. Noe et al., "The Use of Sequence-specific Antibodies to Identify a Secondary Binding Site in Thrombin", J. Biol. Chem., 263, pp. 11729-11735 (1988).
W. Bode et al., "The Refined 1.9 .ANG. Crystal Structure of Human .alpha.-Thrombin: Interaction With D-Phe-Pro-Arg chloromethylketone and Significance of the Tyr-Pro-Pro-Trp Insertion Segment", EMBO J., 8, pp. 3467-3475 (1989).
A. J. B. Brady et al., "Angioplasty and Restenosis", Brit. Med. J., 303, pp. 729-730 (Sep. 1991).
M. O. Dayhoff et al., "A Model of Evolutionary Change in Proteins" in Atlas of Protein Sequence and Structure No. 5, M. O. Dayhoff, ed., National Biomedical Research Foundation, Wash., D.C., 89-100 (1978).
J. W. Fenton, II, "Thrombin Bioregulatory Functions", Adv. Clin. Enzymol., 6, pp. 186-193 (1988).
D. Gurwitz et al., "Thrombin Modulates and Reverses Neuroblastoma Neurite Outgrowth", Proc. Natl. Acad. Sci. USA, 85, pp. 3440-3444 (1988).
R.-S. Huang et al., "Thrombin' Receptor-directed Ligand Accounts for Activation by Thrombin of Platelet Phospholipase C and Accumulation of 3-Phosphorylated Phosphoinositides", J. Biol. Chem., 266, pp. 18435-18438 (Oct. 1991).
D. T. Hung et al., "Thrombion-induced Events in Non-Platelet Cells Are Mediated by the Unique Proteolytic Mechanism Established for the Cloned Platelet Thrombin Receptor", J. Cell Biol., 116, pp. 827-832 (Feb. 1992).
L.-W. Liu et al., "The Region of the Thrombin Receptor Resembling Hirudin Binds to Thrombin and Alters Enzyme Specificity", J. Biol. Chem., 266, pp. 16977-16980 (Sep. 1991).
S. Prescott et al., "Human Endothelial Cells in Culture Produce Platelet-Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). When Stimulated With Thrombin", Proc. Natl. Acad. Sci. USA, 81, pp. 3534-3538 (1984).
E. Skrzypczak-Jankun et al., "Structure of the Hirugen and Hirulog 1 Complexes of .alpha.-Thrombin", J. Mol. Biol., 221, pp. 1379-1393 (1991).
D. N. Tatakis et al., "Thrombin Effects On Osteoblastic Cells -II. Structure-Function Relationships", Biochem. Biophys. Res. Comm., 174, pp. 181-188 (Jan. 1991).
T.-K. H. Vu et al., "Molecular Cloning of a Functional Thrombin Receptor Reveals a Novel Proteolytic Mechanism of Receptor Activation", Cell, 64, pp. 1057-1068 (Mar. 22, 1991).
T.-K. H. Vu et al., "Domains Specifying Thrombin-Receptor Interaction", Nature, 353, pp. 674-677 (Oct. 1991).
J. N. Wilcox, "Thrombin and Other Potential Mechanisms Underlying Restenosis", Circulation, 84, pp. 432-435 (Jul. 1991).
Wolinsky et al., "Use of a Perforated Balloon Catheter to Deliver Concentrated Heparin Into the Wall of the Normal Canine Artery", J. Amer. Coll. Cardiol., 15, pp. 475-481 (Feb. 1990).
Biogen Inc.
Haley, Jr. James F.
Marks Andrew S.
Marshall S. G.
Warden Jill
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