CGS 15435A, a thromboxane synthetase inhibitor with an extended duration of action: a comparison with dazoxiben.
CGS 15435A, a novel thromboxane (Tx) synthetase inhibitor (5-chloro-1-methyl-2-(3-pyridyl)-3-indolhexanoic acid HCl), had a selectivity for Tx synthetase 100,000-fold greater than that for cyclooxygenase, PGI2 synthetase and lipoxygenase enzymes. In conscious beagles, 1 h following a single 3 mg/kg p.o. dose, serum TxB2 was inhibited 95% by CGS 15435 and 82% by dazoxiben (DAZ). Unlike the short acting Tx synthetase inhibitor DAZ, CGS 15435A significantly inhibited TxB2 formation 4, 6, 12 and 24 h after dosing. Serum levels of 6-keto PGF1 alpha and PGE2 were significantly increased following the administration of either drug. CGS 15435A and DAZ were further examined in a model with known Tx involvement. Thrombotic sudden death, produced in anesthetized rabbits by injection of 0.75 mg/kg arachidonic acid (AA) i.v. resulted in a 45% fall in the platelet count and 0% survival. Pretreatment with DAZ (8.6 mumol/kg i.v.) at 0.25 or 2 h pre-AA resulted in 3 and 42% thrombocytopenia and 100 and 0% survival respectively. CGS 15435A (8.6 mumol/kg i.v.) prevented the increases in plasma TxB2 levels, thrombocytopenia and sudden death with pretreatment at 0.25 h (0% thrombocytopenia and 100% survival) or 24 h (11% thrombocytopenia and 83% survival) before AA. These data indicate that CGS 15435A is a potent and selective Tx synthetase inhibitor with a long duration of action, and suggest that the compound could be useful in chronic, non-symptomatic indications of Tx involvement.
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D016861:Cyclooxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003645:Death, Sudden / Q000209:etiology; D015232:Dinoprostone; D004285:Dogs; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D019746:Intramolecular Oxidoreductases; D016859:Lipoxygenase Inhibitors; D010976:Platelet Count / Q000187:drug effects; D011458:Prostaglandins E / Q000097:blood; D011817:Rabbits; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011458:Prostaglandins E; C029166:dazoxiben; C051984:5-chloro-1-methyl-2-(3-pyridyl)-3-indolehexanoic acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; D015232:Dinoprostone