title: The thromboxane A2/prostaglandin endoperoxide receptor antagonist activity of CV-4151, a thromboxane A2 synthetase inhibitor.
abstract: The thromboxane A2/prostaglandin endoperoxide (TXA2/PGH2) receptor antagonist activity of CV-4151, a potent TXA2 synthetase inhibitor, was examined. CV-4151 inhibited guinea pig and human platelet aggregation induced by U-44069 with IC50 values of 1.2 +/- 0.3 X 10(-5) and 1.9 +/- 0.4 X 10(-5) M, respectively, and inhibited the specific binding of [3H]U-46619 to washed guinea pig and human platelets with IC50 values of 1.2 +/- 0.3 X 10(-6) and 5.1 +/- 1.0 X 10(-6) M, respectively. CV-4151 competitively inhibited the contraction of rabbit aortic strips induced by U-44069 with a pA2 value of 5.90. In experiments in mice in vivo, CV-4151 (1 and 10 mg/kg i.v.) significantly inhibited the thrombocytopenia induced by U-44069 in a dose-dependent manner. These results show that CV-4151 has a distinct TXA2/PGH2 receptor antagonist effect, and that this effect together with its inhibition of TXA2 synthetase could be important for the pharmacological action of this compound.
authors.affiliation: Biology Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Imura
authors.forename: Z
authors.initials: Z
authors.lastname: Terashita
authors.forename: Y
authors.initials: Y
authors.lastname: Shibouta
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010976:Platelet Count / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D005229:Fatty Acids, Monounsaturated; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase; C045446:isbogrel