title: Inhibition of uridine phosphorylase: synthesis and structure-activity relationships of aryl-substituted 5-benzyluracils and 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils.
abstract: A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesized and tested for inhibition of murine liver uridine phosphorylase (UrdPase). Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine-induced anemia in animal models. We prepared a series of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a good inhibitor of UrdPase (IC50 of 0.46 microM), to develop a compound with enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substituted 5-benzyluracils found several 5-(3-alkoxybenzyl) analogues of 5-benzyluracil with enhanced potency. The acyclovir side chain, the (2-hydroxyethoxy)methyl group, was substituted on the more potent aryl-substituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC50s of 0.047 and 0.027 microM, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in rats. Plasma uridine levels were elevated 3-9-fold by compound levels that ranged from 8 to 50 microM.
authors.affiliation: Division of Organic Chemistry, Burroughs Wellcome Co., 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: G E
authors.initials: GE
authors.lastname: Boswell
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; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014529:Uridine / Q000097:blood; D014543:Uridine Phosphorylase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D014498:Uracil; D014543:Uridine Phosphorylase; D014529:Uridine