Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors

Details Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors

1998-10-27

2000-09-26

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544349, C07D40112, C07D40312, C07D24138, A61K 31498

Patent

active

061242918

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to the compounds useful for the treatment of thrombotic disorders by the inhibition of serine proteases, typically thrombin, Factor Xa, and/or Factor VIIa. The compounds are characterized as pyrrolo[1,2-a]pyrazine-1,4-dione derivatives.


BACKGROUND OF THE INVENTION

Inordinate thrombus formation on blood vessel walls precipitates acute cardiovascular disease states that are the chief cause of death in economically developed societies. Plasma proteins such as fibrinogen, proteases, and cellular receptors participating in hemostasis have emerged as important factors that play a role in acute and chronic coronary disease, as well as cerebral artery disease, by contributing to the formation of thrombus or blood clots that effectively diminish normal blood flow and supply. Vascular aberrations stemming from primary pathologic states such as hypertension, rupture of atherosclerotic plaques, or denuded endothelium activate biochemical cascades that serve to respond and repair the injury site. Thrombin is a key regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator. However, in pathologic conditions the former is amplified through catalytic activation of cofactors required for thrombin generation as well as activation of Factor XIII necessary for fibrin cross-linking and stabilization.
In addition to its direct effect on hemostasis, thrombin exerts direct effects on diverse cell types that support and amplify pathogenesis of arterial thrombus disease. The enzyme is the strongest activator of platelets, causing them to aggregate and release substances that further propagate the thrombotic cycle. Platelets in a fibrin mesh comprise the principal framework of a white thrombus. Thrombin also exerts direct effects on endothelial cells, causing release of vasoconstrictor substances and translocation of adhesion molecules that become sites for attachment of immune cells. In addition, the enzyme causes mitogenesis of smooth muscle cells and proliferation of fibroblasts. From this analysis, it is apparent that inhibition of thrombin activity constitutes a viable therapeutic approach towards the attenuation of proliferative events associated with thrombosis.
The principal endogenous neutralizing factor for thrombin activity in mammals is Antithrombin III (ATIII), a circulating plasma macroglobulin having low affinity for the enzyme. Heparin exerts clinical efficacy in venous thrombosis by enhancing ATIII/thrombin binding through catalysis. However, heparin also catalyzes inhibition of other proteases in the coagulation cascade, and its efficacy in platelet-dependent thrombosis is largely reduced or abrogated due to inaccessibility of thrombus-bound enzyme. Adverse side effects such as thrombocytopenia, osteoporosis, and triglyceridemnia have been observed following prolonged treatment with heparin.
Hirudin, derived from the glandular secretions of the leech hirido medicinalis, is one of the high molecular weight natural anticoagulant protein inhibitors of thrombin activity (Markwardt F., Cardiovascular Drug Reviews, 1992; 10:211). It is a biopharmaceutical that has demonstrated efficacy in experimental and clinical thrombosis. A potential drawback to the use of Hirudin as a therapeutic agent is likely antigenicity and lack of an effective method of neutralization, especially in view of its extremely tight binding characteristics toward thrombin. The exceedingly high affinity for thrombin is unique and is attributed to a simultaneous interaction with the catalytic site as well as a distal "anion binding exosite" on the enzyme.
Thrombin activity can also be abrogated by Hirudin-like molecules such as hirulog (Maraganore J. M., et al., Biochemistry, 1990; 29:7095) or hirutonin peptides (DiMaio J., et al., J. Med. Chem., 1992; 35:3331).
Thrombin activity can also be inhibited by low molecular weight compounds that compete with fibrinogen for thrombin's catalytic site, thereby inhibiting proteolysis of that prot

REFERENCES:
patent: 4929270 (1990-05-01), Cardellina, II et al.
patent: 5543521 (1996-08-01), Chan et al.

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