Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-04-30
1995-11-28
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540524, 540531, 540533, 540596, 540597, 540602, 540603, 540609, 540610, A61K 3155, C07D40100, C07D40500, C07D40900
Patent
active
054708494
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.
Platelet aggregation is believed to be mediated primarily through the GPIIb-IIIa platelet receptor complex. 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. Fibronectin, vitronectin and thrombospondin are proteins which have also been demonstrated to bind to GPIIb-IIIa. These proteins, all of which contain an Arg-Gly-Asp peptide sequence, are believed to be members of a superfamily of molecules which mediate cellular adhesion and attachment reactions. Fibronectin, for instance, is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls.
Nievelstein et al. (Thromb, and Hemostasis, 58, 2133(1987)) have reported that -RGDS- peptides inhibit thrombin induced aggregation and adhesion of platelets to fibronectin, and may interact through the GPIIb-IIIa complex. U.S. Pat. No. 4,683,291 discloses peptides containing Arg and Lys and an -RGD- sequence which inhibit binding of fibrinogen to platelets and inhibit platelet aggregation. Tetrapeptides which contain the sequence X-Gly-Asp-, wherein X is a guanidine-containing aliphatic carboxylic acid or amino acid residue, are disclosed in EP-A 0 319 506 as inhibitors of platelet aggregation. EP-A 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation. Other peptides and polypeptides which contain an RGD sequence and inhibit fibrinogen binding are disclosed by Plow et al., Blood, 70, 110 (1987), Ginsberg et al., J. Biol. Chem., 260, 3931 (1985), Ruggeri et al., Proc. Natl. Acad. Sci., 83, 5708 (1986) and Haverstick et al., Blood, 66, 946 (1985). Linear and cyclic peptides, the disclosure of which are incorporated herein by reference, are reported in EP-A 0 341 916. There is a need for new molecules which inhibit the binding of GPIIb-IIIa to fibrinogen and inhibit platelet aggregation.
Molecules which mimic a .gamma.-turn in a peptide have bee
REFERENCES:
patent: 4315024 (1982-02-01), Abelson
patent: 4831135 (1989-05-01), Crews et al.
patent: 4966911 (1990-10-01), Clark et al.
patent: 5001113 (1991-03-01), Williams et al.
patent: 5075302 (1991-12-01), Neustadt
patent: 5296489 (1994-03-01), Donald et al.
patent: 5302591 (1994-04-01), Fletcher et al.
Callahan James F.
Huffman William F.
Bond Robert T.
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham Corp.
Venetianer Stephen
LandOfFree
.gamma.-turn peptidomimetics as fibrinogen antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with .gamma.-turn peptidomimetics as fibrinogen antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and .gamma.-turn peptidomimetics as fibrinogen antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2013798