ABSTRACT
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.
Subject(s)
Muscle, Smooth, Vascular/drug effects , Phenylacetates/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Receptors, Thromboxane/antagonists & inhibitors , Sulfonamides/pharmacology , Thromboxane A2/metabolism , Vasodilator Agents/pharmacology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid , Administration, Oral , Animals , Blood Platelets/drug effects , Blood Platelets/metabolism , Blood Pressure/drug effects , Death, Sudden , Dogs , Female , Guinea Pigs , Humans , In Vitro Techniques , Injections, Intravenous , Male , Mice , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Phenylacetates/administration & dosage , Phenylacetates/therapeutic use , Prostaglandin Endoperoxides, Synthetic/pharmacology , Rabbits , Radioligand Assay , Rats , Rats, Wistar , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Thrombocytopenia/chemically induced , Thrombocytopenia/prevention & control , Thromboxane A2/analogs & derivatives , Thromboxane A2/pharmacologyABSTRACT
The antiplatelet and antithrombotic activities of LCB 2853 (sodium 4-[[1-[[[(4-chlorophenyl)sulfonyl]amino]methyl]cyclopentyl] methyl]benzeneacetate, CAS 141335-11-7) a novel thromboxane A2 (TXA2) receptor antagonist were examined after intravenous administration. The correlation between LCB 2853 plasma concentration and ex vivo inhibition of arachidonic acid-induced aggregation was observed in rats, for 4 h, as long as LCB 2853 was detected in plasma by HPLC analysis. Pharmacokinetic parameters were determined. The antithrombotic activity was tested in arterial and venous thrombosis models. In dog coronary stenosis, LCB 2853 shown a very high efficacy (ED50 = 7.2 micrograms/kg), whereas acetylsalicylic acid (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 venous injury and blood stasis, perfused LCB 2853 decreased the weight of thrombi in a dose related manner (ED50 = 220 micrograms/kg/min). In a comparative study, at 250 micrograms/kg/min, ticlopidine was less potent and ASA 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) observed in many models suggest that this compound may have beneficial effects in patients with TXA2-associated disturbances.
