Antiplatelet effect of Z-335, a new orally active and long-lasting thromboxane receptor antagonist

• Published in: European journal of pharmacology 1998-09, Vol.357 (1), p.53-60
• Main Authors: Tanaka, Takao, Fukuta, Yoshihisa, Higashino, Raita, Sato, Ryuichi, Nomura, Yosuke, Fukuda, Youichi, Ito, Shigeru, Takei, Mineo, Kurimoto, Tadashi, Tamaki, Hajime
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - antagonists & inhibitors; Animals; Biological and medical sciences; Biphenyl Compounds - pharmacology; Blood. Blood coagulation. Reticuloendothelial system; Cilostazol; Drug Interactions; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Guinea Pigs; Heptanoic Acids - pharmacology; Humans; Indan derivative; Indans - pharmacology; Indans - therapeutic use; Male; Medical sciences; Mice; Mice, Inbred ICR; Pharmacology. Drug treatments; Phenylacetates - pharmacology; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Pulmonary Embolism - chemically induced; Pulmonary Embolism - prevention & control; Pulmonary thromboembolism; Receptors, Thromboxane - antagonists & inhibitors; Receptors, Thromboxane - metabolism; Sulfonamides - pharmacology; Tetrazoles - pharmacology; Thromboxane A 2 receptor antagonist; Vasoconstrictor Agents; Z-335
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(98)00540-8

We investigated the pharmacological characteristics of Z-335 ((±)-sodium[2-[4-(chlorophenylsulfonylaminomethyl)indan-5-yl]acetate monohydrate), a new indan derivative. Z-335 inhibited the specific binding of [ 3 H ]SQ-29548 to human platelets and guinea pig platelet membranes. The IC 50 values of Z-335 for human platelets and guinea pig platelet membranes were 29.9±3.1 nM with a slope of 1.09±0.05 and 32.5±1.7 nM with a slope of 1.07±0.02, respectively. Z-335 inhibited thromboxane A 2 receptor-mediated human and guinea pig platelet aggregation in vitro and oral administration of this drug to guinea pigs inhibited U-46619- and collagen-induced platelet aggregation for 24 h. Z-335 dose-dependently prevented the occurrence of U-46619-induced pulmonary thromboembolism in mice and the protective effect of this drug (0.3 and 3 mg/kg, p.o.) lasted for 24 h. These results strongly suggest that Z-335 is a potent, orally active and long-lasting thromboxane A 2 receptor antagonist, which may be useful as an antiplatelet drug.