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.
Lardy
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C
Lipha S.A., Research and Development Centre, Lyon, France.
Rousselot
C
C
Chavernac
G
G
Depin
J C
JC
Guerrier
D
D
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000284:Administration, Oral; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003645:Death, Sudden; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014665:Vasodilator Agents; C091835:LCB 2853; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid