Inhibition of uridine phosphorylase. Synthesis and structure-activity relationships of aryl-substituted 1-((2-hydroxyethoxy)methyl)-5-(3-phenoxybenzyl)uracil.
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.
Orr
G F
GF
Division of Organic Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
Musso
D L
DL
Kelley
J L
JL
Joyner
S S
SS
Davis
S T
ST
Baccanari
D P
DP
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*
D004791:Enzyme Inhibitors; D014498:Uracil; D014543:Uridine Phosphorylase; D014529:Uridine