Journal of Medicinal Chemistry p. 68 - 75 (1995)
Update date:2022-08-04
Topics:
Satoh, Yoshitaka
Powers, Colleen
Toledo, Leticia M.
Kowalski, Timothy J.
Peters, Paul A.
et al.
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 ( >95percent) 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.
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