Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Containing at least one abnormal peptide link – e.g. – gamma...
Patent
1984-10-31
1987-01-20
Phillips, Delbert R.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Containing at least one abnormal peptide link, e.g., gamma...
530328, 530329, C07K 502, C07K 706
Patent
active
046380477
DESCRIPTION:
BRIEF SUMMARY
The invention relates to peptide analogues and to the inhibition of thrombogenesis.
Thrombogenesis
Blood clotting depends on a complex series of actions leading finally to cleavage of fibrin from circulating fibrinogen by the protease thrombin, and its subsequent cross linking to form a stable structure. Thrombin production falls in two parts, an `intrinsic` system based on circulating blood components and an `extrinsic` system requiring tissue components. In each, there is a cascade of reactions, a series of inactive `factors` each being converted by proteolytic reaction into the corresponding `a` factor that is itself a proteolytic enzyme effecting the next step.
In the intrinsic system the actions start with circulating Hageman factor (factor XII) undergoing contact activation, becoming bound to damage surfaces or platelet aggregations. A peptide is cleaved from it by the circulating protease kallikrein, forming factor XIIa. Factor XIIa in the presence of circulating high molecular weight kininogen (HMW-K) then (a) cleaves circulating plasma thromboplastin antecedent (factor XI) to give plasma thromboplastin (factor XIa) itself and (b) cleaves circulating pre-kallikrein (Pre-K, Fletcher factor) giving more kallikrein and thus a self-accelerating action. Plasma thromboplastin, in the presence of calcium ions, cleaves circulating Christmas factor (factor IX) to give factor IXa. Factor IXa, with circulating antihaemophilic globulin (AHG, factor VIII) and in the presence of calcium ions and phospholipid micelles from platelets, forms a lipoprotein complex with circulating Stuart factor (factor X) and cleaves it to form factor Xa. Finally factor Xa, with circulating labile factor (factor V) and in the presence of calcium ions and phospholipid micelles, forms a lipoprotein complex with prothrombin (factor II) and cleaves it to form thrombin (factor IIa) itself.
In the extrinsic system, a serum glyco-protein proconvertin (factor VII) is cleaved by several proteases from the intrinsic system (factors XIa and XIIa and kallikrein) to form factor VIIa. Factor VIIa, with a tissue lipoprotein called tissue thromboplastin (factor III), and in the presence of calcium ions, forms a complex with further circulating factor X and cleaves it to form a second source of factor Xa, enhancing thrombin production.
Finally, thrombin from both sources converts circulating fibrinogen to the soluble form of fibrin, which spontaneously polymerizes into filaments and is then cross linked under the action of an enzyme (factor XIIIa) formed, by a second action of thrombin, from circulating fibrin stabilising factor (factor XIII).
In tabular form the accelerating cascade of actions is: ##STR1##
Thrombin
Besides its central action in fibrin clot formation set out above, thrombin is a key factor in the platelet aggregation state of thrombogenesis as discussed for example in H. J. Weiss "Platelets: Pathophysiology and Antiplatelet Drug Therapy" Ch. 1 (Liss, N.Y., 1982) or D. Ogsten and B. Bennett (Eds.) "Haemostasis: Biochemistry, Physiology and Pathology" Ch. 13 (Wiley, 1977). The details are not fully understood, but thrombin is the strongest inducer of the `platelet reaction` (shape change, aggregation, dense granule and .alpha.-granule secretion) responsible for primary haemostasis. The action of thrombin is preceded by its interaction with a specific binding protein in the platelet membrane, and the inhibitors of the present invention also appear to interfere with this binding.
Specific inhibitors of thrombin are thus to be expected to act as highly effective antithrombotic agents and/or anticoagulants, giving alternatives to existing therapeutic and prophylactic agents. Heparin is for example widely used against thrombosis, but it carries a high risk of haemorrhage, is ineffective in many conditions, and gives a variable response from patient to patient and from time to time in a given patient so that careful monitoring is required. Oral anticoagulants also, used particularly for prophylaxis and control of venous thrombosis, ta
Jones David M.
Szelke Michael
Aktiebolaget Hassle
Phillips Delbert R.
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