Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
Satoh
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Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Powers
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Toledo
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Kowalski
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Kimble
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D000284:Administration, Oral; D000818:Animals; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D006168:Guinea Pigs; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D006918:Hydroxyurea / Q000031:analogs & derivatives*; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism
C091725:2-((N-(aminocarbonyl)-N-hydroxyamino)methyl)-1,4-benzodioxan; D004146:Dioxanes; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D006918:Hydroxyurea