Pharmacological characterization of FCE 27262, a combined thromboxane synthase inhibitor and PGH2/TXA2 receptor antagonist.
The literature supports the hypothesis that the association of a thromboxane (TX)A2 synthase inhibitor and a PGH2/TXA2 receptor antagonist has a superior antithrombotic effect when compared to both aspirin and single agent alone; a compound endowed with the dual mechanism of action might therefore be of therapeutic value for the management of thrombotic disorders. FCE 27262, an imidazol-1-yl-ethylideneaminooxypentanoic acid, displaces in vitro the binding of [3H]SQ 29,548 to washed human platelets (IC50 = 6.0 +/- 0.6 x 10(-8) M) and antagonizes human platelet aggregation induced by U 46619 in PRP with an IC50 (95% confidence limits) of 4.5(3.3-5.1) x 10(-7) M. It also selectively antagonizes the isolated vessel contraction induced by U 46619. In the rat aorta the Kb (95% confidence limits) was 1.6(0.6-4.3) x 10(-7) M. Additionally it inhibits in vitro TXB2 production in rat and human whole blood, the IC50 being, respectively, 5.9(3.3-9.6) x 10(-8) M and 3.8(2.9-5.0) x 10(-8) M. When administered orally to fed rats it also inhibits ex vivo TXB2 production in whole blood during clotting, the ID50 being 0.62(0.4-0.8) mg/kg. Both in vitro and ex vivo the effect of FCE 27262 on TXA2 synthase was selective, the production of PGE2, the product of a different isomerase from the common precursors, PG-endoperoxides, being concomitantly enhanced. In a canine model of electrically-induced coronary thrombosis, FCE 27262 (1 mg/kg i.v.) inhibits ex vivo TXB2 synthesis (> 95%), antagonizes U 46619-induced platelet aggregation and prolongs occlusion time (controls: 72 +/- 8 min, FCE 27262: 215 +/- 38 min; p < 0.01). In the same model both aspirin (5 mg/kg i.v.) and a pure PGH2/TXA2 receptor antagonist (L 670596), at a dose giving a similar degree of TXA2 synthase inhibition and receptor blockade, respectively, are significantly less effective. Thus, FCE 27262 combines thromboxane synthase inhibition and PGH2/TXA2 receptor antagonism in one molecule, resulting in enhanced antithrombotic activity. FCE 27262 thus may be an appropriate pharmacological tool to test the therapeutic potential of the dual mechanism of action.
Cardiovascular Department, Farmitalia Carlo Erba S.r.l., Nerviano, Milan, Italy.
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Vaghi
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Pierucci
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Salvati
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D003328:Coronary Thrombosis / Q000188:drug therapy; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D002227:Carbazoles; D005343:Fibrinolytic Agents; D007093:Imidazoles; D010421:Pentanoic Acids; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C061299:L 670596; C087932:FCE 27262; D013930:Thromboxane-A Synthase; C060219:ridogrel; D001241:Aspirin