Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1994-04-29
1996-07-23
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540451, C07K 502, C07K 506, C07K 508, C07K 1500, C07D24502, F61K 3702
Patent
active
055391044
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to novel compounds which inhibit platelet aggregation, pharmaceutical compositions containing the compounds and methods of using the compounds for inhibiting platelet aggregation. A method of using the compounds of this invention in combination with fibrinolytic agents is also disclosed.
BACKGROUND OF THE INVENTION
A thrombus is the result of processes which initiate the coagulation cascade. It is composed of an aggregation of platelets enmeshed in a polymeric network of fibrin. This process is normally initiated as a consequence of tissue injury and has the effect of slowing or preventing blood flow in a vessel. Etiological factors which are not directly related to tissue injury, such as atherosclerotic plaque, inflammation of the blood vessels (phlebitis) and septicemia, may also initiate thrombus formation. In some instances, the inappropriate formation of a thrombus, and subsequent decrease in blood flow, may have pathological consequences, such as stroke, pulmonary embolism and heart disease.
Platelets play a major role in thrombus formation. Current antithrombotic therapy employs agents that modify the platelet/endothelial cell arachidonate-prostaglandin system, such as prostacyclin analogues, cyclooxygenase inhibitors, thromboxane synthesis inhibitors and thromboxane receptor antagonists; and anti-coagulants, such as heparin. These agents inhibit one or both of two discernible phases of platelet aggregation. The primary phase, which is a response to chemical stimuli, such as ADP (adenosine diphosphate), collagen, epinephrine or thrombin, causes initial activation of the platelets. This is followed by a secondary phase, which is initiated by the platelets themselves, and is characterized by thromboxane A.sub.2 (TxA.sub.2) synthesis and the release of additional ADP from platelet storage granules, which further activates platelets.
Prostacyclin, also called prostaglandin I.sub.2 (PGI2), and stable PGI.sub.2 analogues inhibit both the primary and secondary phases of platelet aggregation. However, use of such analogues has been associated with undesirable changes in blood pressure. See Aiken, et al., Prostaglandins, 19, 629-43 (1980).
Cyclooxygenase inhibitors and thromboxane synthetase inhibitors act to block the production of TxA.sub.2. TxA.sub.2 antagonists block the effects of TxA.sub.2 by binding the TxA.sub.2 receptor. These therapies act only upon the secondary stage of platelet activation. Use of cyclooxygenase inhibitors has been associated with ulcerogenesis and an adverse effect upon prostacyclin synthesis.
Heparin prevents the activation of fibrinogen by thrombin and thereby prevents the activation of the GPIIb-IIIa receptor by thrombin. This inhibits only the primary phase of platelet aggregation and has little effect upon activation of platelets by other means, such as collagen, ADP and epinephrine.
Cyclooxygenase inhibitors, prostaglandin analogues and heparin all inhibit platelet aggregation indirectly by inhibiting the primary or secondary phase of platelet/fibrinogen activation. There is therefore a need for selective therapeutic products which block platelet aggregation directly, whether it arises from the primary or secondary phase of platelet activation.
Platelet aggregation is believed to be mediated primarily through the GPIIb-IIIa platelet receptor complex, which is also called the fibrinogen receptor. Von Willebrand factor, a plasma protein, and fibrinogen are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets. Preventing the binding and crosslinking of GPIIb-IIIa receptors is believed to be method of inhibiting platelet aggregation.
GPIIb-IIIa is a member of a larger class of receptor proteins, called integrins, which mediate adhesive functions. Fibronectin, vitronectin and thrombospondin are proteins which have also been demonstrated to bind to GPIIb-IIIa. Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the str
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Callahan James F.
Huffman William F.
Higel Floyd D.
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham Corp.
Venetianer Stephen
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