A-69412

Oral doses of A-69412 are found to inhibit leukotriene production in a number of species. For example, A-69412 is found to be a potent long-acting inhibitor of leukotriene formation in vivo in the rat (oral ED₅₀=5 mg/kg). A-69412 is remarkably potent in the dog, giving nearly complete inhibition through 16 h after a single 5 mg/kg dose. Plasma concentrations in the dog studies are 38 μM at 0.5 h after dosing and 5 μM at 16 h. These data are consistent with the 100% inhibition seen ex vivo at 0.5 h post-dosing and the 90% inhibition seen at 16 h. As would be expected from the pharmacokinetic results, A-69412 is clearly superior to zileuton in the cynomolgus monkey. A-69412 gave >50% inhibition of ex vivo LTB₄ biosynthesis in the monkey for 8 h, while zileuton is effective only in the first 2 h after oral dosing. An anaphylactic reaction in the rat peritoneal cavity of passively sensitized animals produces large amounts of sulfidopeptide leukotrienes. Given as an oral solution, A-69412 dose-dependently inhibits leukotriene production in the peritoneal cavity of the rat. In one of the experiments, blood levels of A-69412 are measured. These values range from 4 to 100 μM with doses ranging from 2 to 50 mg/kg. A-69412 also significantly inhibits the reaction if dosed (10 mg/kg) at times up to 8 h before challenge. Plasma concentrations of A-69412 are measured in the time course studies and are found to range from 44 μM at 0.5 h to 10 μM at 8 h after dosing^[1].