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.

Synthesis and Structure–Activity Relationships of FAAH Inhibitors: Cyclohexylcarbamic Acid Biphenyl Esters with Chemical Modulation at the Proximal Phenyl Ring

“…Biphenyl‐3‐ols substituted at the 4 or 6 positions 1 a , c , e and 3′‐phenoxybiphenyl‐3‐ol ( 1 l ) were obtained by hydrolysis of the corresponding 3‐methoxyaryls with boron tribromide (for compounds 1 a , e ), lithium chloride16 (for compound 1 c ), or hydiodric acid (for compound 1 l ). The 3‐methoxyaryl compounds were prepared by Suzuki cross‐coupling of phenylboronic acid ( 7 ) and compounds 6 e , l 17 (Scheme 4), or by nitration of 3‐methoxybiphenyl18 in the case of compounds 8 a , c (for which the compound numbering scheme follows analogously that of compounds 2 in Table 1). Compound 1 f was synthesized by the reaction of 7 and 3‐bromo‐4‐methylphenol ( 6 f )19 (Scheme 4).…”

Zinc Triflate Catalyzed C-Benzylation: Chemo- and Regioselective Route to Amido Substituted Diaryl and Arylheteroarylmethanes

“…Benzylation of 1,3-dimethyluracil gave 5-(4-methoxybenzyl)-1,3-dimethylpyrimidine-2,4­(1 H ,3 H )-dione ( 5g ) in 72% yield. These 5-benzyl uracil derivatives are biologically important as antiviral agents, and for inhibiting the mammalian enzyme uridine phosphorylase responsible for degradation of floxuridine, a known anticancer drug …”

Flexible Nucleobase Analogues: Novel Tools for Exploring Nucleic Acids

“…These compounds were screened against uridine phosphorylase (UrdPase), since inhibition of this enzyme is thought to enhance the therapeutic effect of nucleoside drugs such as 5-fluorouracil (Orr et al 1995). Later analogues exhibited increased inhibition of UrdPase, with enhanced pharmacodynamic effects compared to those noted for BAU (Orr et al 1997).…”