title: 5-Lipoxygenase inhibitors: synthesis and structure-activity relationships of a series of 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-ones.
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.
authors.affiliation: Abbott Laboratories, Immunoscience Research Area, Abbott Park, Illinois 60064-3500, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Bhatia
authors.forename: C D
authors.initials: CD
authors.lastname: Brooks
authors.forename: A
authors.initials: A
authors.lastname: Basha
authors.forename: J D
authors.initials: JD
authors.lastname: Ratajczyk
authors.forename: B P
authors.initials: BP
authors.lastname: Gunn
authors.forename: J B
authors.initials: JB
authors.lastname: Bouska
authors.forename: C
authors.initials: C
authors.lastname: Lanni
authors.forename: P R
authors.initials: PR
authors.lastname: Young
authors.forename: R L
authors.initials: RL
authors.lastname: Bell
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000097:blood; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology; D004285:Dogs; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D015471:Leukemia, Basophilic, Acute / Q000201:enzymology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008706:Methemoglobin / Q000032:analysis; D015394:Molecular Structure; D051381:Rats; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep; D013025:Glycine max / Q000201:enzymology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C101727:1-phenylperhydro-1,2,4-triazin-3-one; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D014227:Triazines; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D008706:Methemoglobin; D001092:Arachidonate 12-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase