title: Inhibition of uridine phosphorylase. Synthesis and structure-activity relationships of aryl-substituted 1-((2-hydroxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil.
abstract: Structure-activity relationship studies on a series of 1-((2-hydroxyethoxy)methyl)-5-(3-(substituted-phenoxy)benzyl)uracils as inhibitors of murine liver uridine phosphorylase have led to compounds with IC50s as low as 1.4 nM. The two most potent compounds, 10j (3-cyanophenoxy) and 11f (3-chlorophenoxy) were tested in vivo for effects on steady-state concentrations of circulating uridine in mice and rats. Both compounds were substantially more efficacious than BAU (5-benzylacyclouridine) both in vitro and in vivo.
authors.affiliation: Division of Organic Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Orr
authors.forename: D L
authors.initials: DL
authors.lastname: Musso
authors.forename: J L
authors.initials: JL
authors.lastname: Kelley
authors.forename: S S
authors.initials: SS
authors.lastname: Joyner
authors.forename: S T
authors.initials: ST
authors.lastname: Davis
authors.forename: D P
authors.initials: DP
authors.lastname: Baccanari
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives*; D014529:Uridine / Q000097:blood; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D014498:Uracil; D014543:Uridine Phosphorylase; D014529:Uridine