title: Pharmacological properties of the novel anti-platelet aggregating agent 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid.
abstract: Various pharmacological properties of a new antiplatelet aggregating agent, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid (E-5510), were examined in order to elucidate its mode of action, Firstly, the inhibitory effect on in vitro aggregation of platelets from humans and various experimental animals was studied. E-5510 inhibited human platelet aggregation induced by collagen, arachidonic acid, adenosine diphosphate (ADP), platelet activating factor (PAF) and epinephrine. Thrombin-induced platelet aggregation, which was not inhibited by acetylsalicylic acid (ASA) or the thiazole drug, 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl) thiazole, was inhibited by E-5510. E-5510 inhibited collagen-induced platelet aggregation in platelet-rich plasma (PRP) from guinea pigs, beagle dogs and monkey to the same degree as in human PRP, but its effect was weaker in rat PRP. Human platelet adhesion to a collagen-coated plastic disk and thrombin-induced adenosine triphosphate (ATP) release from human platelets were also inhibited by this compound. Next, the ex vivo anti-platelet effect of E-5510 was examined in guinea pigs and beagle dogs. E-5510 was the most potent among the tested drugs (ticlopidine, ASA, cilostazol and the thiazole drug. The anti-platelet effect of this compound appeared within 1 h and lasted more than 8 h after oral administration. The above results suggest that E-5510 may antagonize platelet activation by inhibiting phospholipase C and/or A2, which results in suppression of both phosphatidylinositol breakdown and arachidonic acid release from phospholipids, as well as by inhibiting cyclooxygenase. E-5510 exerted its anti-platelet action without affecting prostaglandin I2 production in the blood vessels. It is considered that E-5510 has a highly potent anti-platelet aggregating effect and a unique multi-site mode of action. This compound is a promising candidate as an antithrombotic drug for clinical use.
mesh_terms: D000818:Animals; D004285:Dogs; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010743:Phospholipids / Q000097:blood; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D013045:Species Specificity
chemical_list: D005229:Fatty Acids, Monounsaturated; D010743:Phospholipids; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; C054678:Satigrel