PHARMACODYNAMICS AND ANTITHROMBOTIC EFFECTS AFTER INTRAVENOUS ADMINISTRATION OF THE NEW THROMBOXANE A(2) RECEPTOR ANTAGONIST SODIUM NYL]AMINO]METHYL]CYCLOPENTYL]METHYL]BENZENEACETATE

The antiplatelet and antithrombotic activities of LCB 2853 (sodium (4- chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) a novel thromboxane A(2) (TXA(2)) receptor antagonis t were examined after intravenous administration. The correlation betw een LCB 2853 plasma concentration and ex vivo inhibition of arachidoni c acid-induced aggregation was observed in rats, for 4 h, as long as L CB 2853 was detected in plasma by HPLC analysis. Pharmacokinetic param eters were determined. The antithrombotic activity was tested in arter ial and venous thrombosis models. In dog coronary stenosis, LCB 2853 s hown a very efficacy (ED(50) = 7.2 mu g/kg), whereas acetylsalicylic a cid (ASA) was only active at 3.2 mg/kg and ticlopidine was ineffective at 12.8 mg/kg. In rat venous thrombosis induced by combination of ven ous injury and blood stasis, perfused LCB 2853 decreased the weight of thrombi in a dose related manner (ED(50) = 220 mu g/kg/min). In a com parative study, at 250 mu g/kg/min, ticlopidine was less potent and AS A failed to show any protection. The potent immediate efficacy of LCB 2853 and the advantageous comparisons with ASA (which was ineffective in some models) or ticlopidine (which needs metabolization lag time) o bserved in many models suggest that this compound may have beneficial effects in patients with TXA(2)-associated disturbances.