5-LIPOXYGENASE INHIBITORS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A SERIES OF 1-ARYL-2H,4H-TETRAHYDRO-1,2,4-TRIAZIN-3-ONES

Synthetic routes were developed to access a variety of novel 1-aryl-2H ,4H-tetrahydro-1,2,4-triazin-3-one analogs which were evaluated as 5-l ipoxygenase (5-LO) inhibitors. The parent structure, 1-phenylperhydro- 1,2,4-triazin-3-one (4), was found to be a selective inhibitor of 5-LO in broken cell, intact cell, and human blood assays with IC50 values of 5-21 mu M. In a rat anaphylaxis model, 4 blocked leukotriene format ion with an ED(50) = 7 mg/kg when administered orally. Compound 4 exhi bited selectivity for inhibition of 5-LO with little activity against related enzymes: 12-LO from human platelets, 15-LO from soybean, and c yclooxygenase (COX) from sheep seminal vesicle. In pilot subacute toxi city testing, 4 did not produce methemoglobinemia in rats (400 mg/kg p o daily for 9 days) or in dogs (200 mg/kg po daily for 28 days). These results indicated that the triazinone structure provided a 5-LO inhib itor template devoid of the toxicity problems observed in the related phenidone (1) and pyridazinone (3) classes of 5-LO inhibitors. The par ent compound 4 is a selective, orally bioavailable 5-LO inhibitor whic h can serve as a useful reference standard for in vivo pharmacological studies involving leukotriene-mediated phenonmena.