1. Academic Validation
  2. 5-Lipoxygenase inhibitors: synthesis and structure-activity relationships of a series of 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-ones

5-Lipoxygenase inhibitors: synthesis and structure-activity relationships of a series of 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-ones

  • J Med Chem. 1996 Sep 27;39(20):3938-50. doi: 10.1021/jm960372b.
P A Bhatia 1 C D Brooks A Basha J D Ratajczyk B P Gunn J B Bouska C Lanni P R Young R L Bell G W Carter
Affiliations

Affiliation

  • 1 Abbott Laboratories, Immunoscience Research Area, Abbott Park, Illinois 60064-3500, USA.
Abstract

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-lipoxygenase (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 microM. In a rat anaphylaxis model, 4 blocked leukotriene formation with an ED50 = 7 mg/kg when administered orally. Compound 4 exhibited selectivity for inhibition of 5-LO with little activity against related enzymes: 12-LO from human platelets, 15-LO from soybean, and cyclooxygenase (COX) from sheep seminal vesicle. In pilot subacute toxicity testing, 4 did not produce methemoglobinemia in rats (400 mg/kg po 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 inhibitor template devoid of the toxicity problems observed in the related phenidone (1) and pyridazinone (3) classes of 5-LO inhibitors. The parent compound 4 is a selective, orally bioavailable 5-LO inhibitor which can serve as a useful reference standard for in vivo pharmacological studies involving leukotriene-mediated phenonmena.

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