Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor

Details Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor

1994-09-26

1998-01-06

Bond, Robert T.

Electric lamp and discharge devices: consumable electrodes

With economizer

514219, 540497, 540498, C07D48704, A61K 3155

Patent

active

057058903

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to tricyclic integrin receptor inhibitors, especially inhibitors of the platelet GPII.sub.b III.sub.a receptor. Specifically, the invention is directed to 1,4-benzodiazepines having one or more 5- or 6-member heterocycle fused to the diazepine moiety that act as antagonists of the final common pathway of platelet aggregation. These antagonists act as potent antithrombotics. The invention further relates to therapeutic applications of these tricyclic inhibitors in diseases for which blocking platelet aggregation is indicated.


BACKGROUND OF THE INVENTION

Platelets are particles found in whole blood that initiate and provide the structural basis for the hemostatic plug necessary to stop bleeding. Platelets depend on adhesive interactions with extracellular proteins and other cells for proper function (see Hawiger, J. Atherosclerosis Reviews 21:165-186 (1990) and Roth J. R. Immunology Today 13(2):100-105 (1992)). The external platelet plasma membrane surface is covered with a variety of membrane bound glycoproteins, many of which have recognition and adhesive functions. Perhaps the most abundant platelet membrane adhesive proteins belong to the integrin superfamily which include the glycoproteins; GPII.sub.b III.sub.a, GPI.sub.a II.sub.a, GPI.sub.c II.sub.a, GPI.sub.b IX, and the fibronectin and vitronectin receptors (Hynes, R. O., Cell, 48: 549 (1987). Each integrin receptor is an .alpha..beta. heterodimer displaying characteristic affinity and specificity toward various protein ligands found in serum and/or the extracellular matrix including; von Willebrand factor (vWF), collagen, entactin, tenascin, fibronectin (Fn), vitronectin (Vn), and laminin, as well as fibrinogen (Fg) and thrombospondin (see Kieffer et al., Ann. Rev. Cell Biol. 6:329-357(1990) and Ruoslahti, J. Clin. Invest., 87:1-5 (1991)). The most abundant integrin found on the surface of normal platelets is GPII.sub.b III.sub.a comprising about 50,000 molecules per platelet and representing about 2% of the total platelet protein. GPII.sub.b III.sub.a is a non-covalent, calcium ion dependent heterodimeric complex (Jennings, et al., J. Biol. Chem. 257: 10458 (1982)) that is restricted in distribution to platelets and other cells of the megakaryocytic lineage (Kieffer et al., supra). On activated platelets, GPII.sub.b II.sub.a promiscuously binds a number of protein ligands with varying affinities, including; fibrinogen, fibronectin, von Willebrand factor, vitronectin and thrombospondin (Plow et al., Biochemistry of Platelets, Phillips and Shuman eds., p. 225-256, least one tripeptide sequence Arg-Gly-Asp which is commonly referred to as the "recognition sequence". It is believed the most important interactions mediating platelet aggregation involve GPII.sub.b III.sub.a binding with the trinodular fibrinogen and, to a lesser extent, with the filamentous von Willebrand factor (Kieffer et al. , supra and Albeda et al., The FASEB
GPII.sub.b III.sub.a binding to its natural ligands can be inhibited to varying degrees by peptides and proteins containing the amino acid recognition sequences; Arg-Gly-Asp (RGD) (Ruoslahti, supra and EPO 0368486, assigned to Merck & Co.), Lys-Gly-Asp (KGD), and the fibrinogen .gamma.-chain carboxy-terminal dodecapeptide HHLGGAKQAGDV and analogues
Many common human disorders are characteristically associated with a hyperthrombotic state leading to intravascular thrombi and emboli. These are a major cause of medical morbidity, leading to infarction, stroke and phlebitis, and of mortality from stroke and pulmonary and cardiac emboli. Patients with atherosclerosis are predisposed to arterial thromboembolic phenomena for a variety of reasons. Atherosclerotic plaques form niduses for platelet plugs and thrombi that lead to vascular narrowing and occlusion, resulting in myocardial and cerebral ischemic disease. This may happen spontaneously or following procedures such as angioplasty or endarterectomy. Thrombi that break off and are released into the circulation cause infarcti

REFERENCES:
patent: 5250679 (1993-10-01), Blackburn et al.
patent: 5403836 (1995-04-01), Blackburn et al.
patent: 5493020 (1996-02-01), Blackburn et al.
Ager et al., "Central Nervous System Activity of a Novel Class of Annelated 1,4-Benzodiazephines, Aminomethylene-2,4-dihydro-1H-imidazo 20(8):1035-1041 (1977).
Hawiger, "Platelet-Vessel Wall Interactions Platelet Adhesion and Aggregation" Atherosclerosis Reviews 21:165-186 (1990).
Hynes, "Integrins: A Family of Cell Surface Receptors" Cell 48:549-554 (1987).
Kieffer et al., "Platelet Membrane Glycoproteins: Functions in Cellular Interactions" Annu. Rev. Cell Biol. 6:329-357 (1990).
Roth, "Platelets and blood vessels: the adhesion event" Immunology Today 13(3):100-105 (1992).
Ruoslahti, "Integrins" J. Clin. Invest. 87:1-5 (1991).

Affiliated with

Also associated with

Rating

Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2332143