INHIBITION OF URIDINE PHOSPHORYLASE - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF ARYL-SUBSTITUTED 5-BENZYLURACILS AND 1-[(2-HYDROXYETHOXY)METHYL]-5-BENZYLURACILS

A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesiz ed and tested for inhibition of murine liver uridine phosphorylase (Ur dPase). Inhibitors of UrdPase are reported to enhance the chemotherape utic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ame liorate zidovudine-induced anemia in animal models. We prepared a seri es of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a g ood inhibitor of UrdPase (IC50 of 0.46 mu M), to develop a compound wi th enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substit uted 5-benzyluracils found several 5-(3-alkoxybenzyl) analogues of 5-b enzyluracil with enhanced potency. The acyclovir side chain, the (2-hy droxyethoxy)methyl group, was substituted on the more potent aryl-subs tituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy ) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC(50)s of 0.047 and 0.027 mu M, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in r ats. Plasma uridine levels were elevated 3-9-fold by compound levels t hat ranged from 8 to 50 mu M.