The mechanism of action of KBT-3022, a new antiplatelet agent.
1. The mechanism of action of a new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate) and its active main metabolite, desethyl KBT-3022, was investigated. 2. KBT-3022 and desethyl KBT-3022 inhibited cyclooxygenase from ovine seminal gland with IC50 values of 0.69 and 0.43 microM, respectively. 3. At concentrations higher than those required for cyclooxygenase inhibition, desethyl KBT-3022 inhibited cAMP-phosphodiesterase, specific binding of U46619, and release of phosphatidic acid from thrombin-stimulated platelets. 4. Oral administration of KBT-3022 inhibited the production of thromboxane B2 during blood coagulation more potently than the production of 6-keto-prostaglandin F1 alpha from aortic strips in guinea pigs. 5. These findings suggest that KBT-3022 may inhibit platelet activation principally via the inhibition of cyclooxygenase by desethyl KBT-3022.
Matsuo
K
K
New Drug Research Laboratories, Kanebo, Ltd., Osaka, Japan.
Yokota
K
K
Yamashita
A
A
Oda
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D006168:Guinea Pigs; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism; D008297:Male; D010712:Phosphatidic Acids / Q000096:biosynthesis; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D010712:Phosphatidic Acids; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011758:Pyrroles; D013844:Thiazoles; C064847:KB 3022; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D013917:Thrombin; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase