CGS 15435A, a thromboxane synthetase inhibitor with an extended duration of action: a comparison with dazoxiben.

Abstract

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.

• Authors: R W Olson, D S Cohen, E C Ku, E F Kimble, H B Renfroe, E F Smith 3rd
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 133 Issue 3 Pg. 265-73 (Jan 20 1987) ISSN: 0014-2999 [Print] Netherlands
• PMID: 3104066 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Cyclooxygenase Inhibitors
• Imidazoles
• Indoles
• Lipoxygenase Inhibitors
• Prostaglandins E
• dazoxiben
• 5-chloro-1-methyl-2-(3-pyridyl)-3-indolehexanoic acid
• Thromboxane B2
• 6-Ketoprostaglandin F1 alpha
• Cytochrome P-450 Enzyme System
• Epoprostenol
• Intramolecular Oxidoreductases
• prostacyclin synthetase
• Thromboxane-A Synthase
• Dinoprostone

Topics

• 6-Ketoprostaglandin F1 alpha (blood)
• Animals
• Cyclooxygenase Inhibitors
• Cytochrome P-450 Enzyme System
• Death, Sudden (etiology)
• Dinoprostone
• Dogs
• Epoprostenol (antagonists & inhibitors, biosynthesis)
• Imidazoles (pharmacology)
• In Vitro Techniques
• Indoles (pharmacology, toxicity)
• Intramolecular Oxidoreductases
• Lipoxygenase Inhibitors
• Platelet Count (drug effects)
• Prostaglandins E (blood)
• Rabbits
• Thromboxane B2 (blood)
• Thromboxane-A Synthase (antagonists & inhibitors)