Antiaggregant and antivasospastic properties of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate

LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) was demonstrated to be a potent thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonist in in vitro, ex vivo and in vivo experiments. The specific mechanism of action was studied in [3H]SQ 29548 receptor binding studies (pKi = 7.93) and was shown to be of competitive nature in U 46619-induced platelet aggregation (pA2 = 6.82). TXA2-dependent platelet rich plasma (PRP) aggregation (U 46619, arachidonic acid (AA), collagen, ADP or serotonin second phase) was inhibited in vitro in humans (IC50:0.037-0.65 mumol/l) and different animal species, as well as ex vivo i.v. rat and p.o. guinea-pig AA-induced aggregation (ED50 = 48 and 57 micrograms/kg). The U 46619-induced contractions of aorta, caudal artery and trachea were inhibited in a dose-dependent way (IC50 = 0.07, 0.02 and 0.5 mumol/l respectively). In vivo, both against platelet aggregation and vasoconstriction, LCB 2853 showed an ED50 lower than 1 mg/kg i.v. in rat AA-induced thrombocytopenia or U 46619-induced hypertension (ED50 = 0.25 and 0.16 mg/kg) as well as in AA-induced sudden death in the mouse (ED50 = 0.44 mg/kg). The U 46619-induced bronchoconstriction was blocked after i.v. administration of LCB 2853 (ED50 = 18.4 micrograms/kg). The duration of action observed in different models was 6 h by oral route and between 3 and 5 h by intravenous route. These properties in TXA2-dependent models led to further investigations of the antithrombotic activity of this novel TXA2 antagonist.