Synthesis of original drugs with a dual mode of action : thromboxane receptor antagonist and thromboxane synthase inhibitor. These compounds are promising antiplatelet or anti-asthmatic agents.

Since torasemide, a loop diuretic designed in our pharmaceutical research laboratories, presenting a slight thromboxane A2 (TXA2) receptor antagonism on canine coronary artery, we developed a series of TXA2 modulators. TXA2 is an arachidonic acid metabolite derived from the cyclooxygenase pathway and characterized by potent proaggregatory, vaso- and bronchoconstrictor properties. This eicosanoid is involved in various cardiovascular, pulmonary and renal pathologies. More than sixty molecules were synthesized and their affinity for TP receptors determined. This work led to the synthesis of original drugs with a dual mode of action: thromboxane receptor antagonist and thromboxane synthase inhibitor such as BM-573. Indeed, in several physiopathological models performed in pigs, BM-573 was demonstrated to prevent myocardial infarction induced by occlusive thrombus of the LAD, to reduce the early toxic phase (pulmonary hypertension) of both the septic shock induced by LPS injection and pulmonary embolism. Moreover, BM -567 was demonstrated to prevent bronchoconstriction induced in vivo in guinea pigs. Finally, our thromboxane modulators were found active in preventing angiogenesis in different in vitro models and to inhibit platelet aggregation induced by tumor cells, suggesting an interesting potential as anti-metastatic agents.

Early Stage

WO 00/42004

Research collaboration for license agreement