THE INHIBITORY EFFECT OF 2-THIENYL 2′-HYDROXYPHENYL KETONE (C85) ON PLATELET THROMBOXANE FORMATION

• Published in: Thrombosis research Vol. 84; no. 2; pp. 83 - 95
• Main Authors: Chou, Tz-Chong, Hsu, Ling-Yih, Yen, Mao-Hsiung, Ding, Yu-An
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Ltd 15.10.1996; Elsevier Science
• Subjects: 2-heteroaryl 2′-substituted-phenyl ketone derivatives; Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - physiology; Blood. Blood coagulation. Reticuloendothelial system; Calcium - metabolism; cyclooxygenase activity; Dinoprostone - biosynthesis; Fura-2; Humans; Ketones - chemistry; Ketones - pharmacology; Medical sciences; Mice; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; platelet function; Rabbits; Thiophenes - chemistry; Thiophenes - pharmacology; Thromboxane A 2; Thromboxane B2 - biosynthesis; Thromboxane A 2; cyclooxygenase activity; 2-heteroaryl 2′-substituted-phenyl ketone derivatives; platelet function; Human; Prostaglandin-endoperoxide synthase; Intramolecular oxidoreductases; Enzyme; Enzyme inhibitor; Ketone; In vitro; Antiplatelet agent; Aggregation; Platelet; Isomerases; Thromboxane-A synthase; Oxidoreductases; Mechanism of action
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/0049-3848(96)00164-8

A new synthetic compound, 2-thienyl 2′-hydroxyphenyl ketone (C85), was demonstrated as an antiplatelet agent. In rabbit washed platelets, C85 dose-dependently inhibited arachidonic acid(AA), collagen and platelet activating factor(PAF)-induced platelet aggregation and ATP release with IC 50 values of 0.6±0.2, 20.5±8.3 and 145.6±28.6μM respectively. In human platelet rich plasma(PRP), C85 selectively inhibited the second phase of platelet aggregation and ATP release induced by epinephrine. The formation of platelet thromboxane B 2 (TXB 2) caused by AA, collagen and thrombin was completely inhibited by C85(10 μM). C85 could significantly reduce cyclooxygenase activity as reflected by attenuation of prostaglandin E 2(PGE 2) formation. C85 also possess weakly inhibitory effect on thromboxane synthase as reflected by slightly inhibition of prostaglandin H 2 (PGH 2)-induced TXB 2 formation. In Fura-2/AM loaded platelets, the rise of intracellular calcium level challenged by AA, collagen and thrombin were inhibited by C85. The C85(10 μM) also significantly suppressed the phosphoinositide breakdown induced by AA and collagen. In vivo, C85(50μg/Kg i.p.) produced a marked prolongation of tail bleeding time than that treated by indomethacin in mice. In summary, the antiplatelet mechanism of C85 is mainly inhibition of platelet cyclooxygenase activity and partly inhibition of thromboxane synthase activity and lead to diminution of TXA 2 formation. Copyright © 1996 Elsevier Science Ltd