Antiplatelet effect of Z-335, a new orally active and long-lasting thromboxane receptor antagonist.
We investigated the pharmacological characteristics of Z-335 ((+/-)-sodium[2-[4-(chlorophenylsulfonylaminomethyl)indan-5-yl]ace tate monohydrate), a new indan derivative. Z-335 inhibited the specific binding of [3H]SQ-29548 to human platelets and guinea pig platelet membranes. The IC50 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 A2 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 A2 receptor antagonist, which may be useful as an antiplatelet drug.
Tanaka
T
T
Central Research Laboratories, Zeria Pharmaceutical, Saitama, Japan.
Fukuta
Y
Y
Higashino
R
R
Sato
R
R
Nomura
Y
Y
Fukuda
Y
Y
Ito
S
S
Takei
M
M
Kurimoto
T
T
Tamaki
H
H
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D000077407:Cilostazol; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010648:Phenylacetates / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000517:prevention & control; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D014662:Vasoconstrictor Agents
D001713:Biphenyl Compounds; D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; D007189:Indans; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; C115527:Z 335; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C060013:vapiprost; D000077407:Cilostazol; C051762:daltroban