Synthesis and evaluation of S-acyl-2-thioethyl esters of modified nucleoside 5'-monophosphates as inhibitors of hepatitis C virus RNA replication

被引:32
作者
Prakash, TP
Prhavc, M
Eldrup, AB
Cook, PD
Carroll, SS
Olsen, DB
Stahlhut, MW
Tomassini, JE
MacCoss, M
Galloway, SM
Hilliard, C
Bhat, B
机构
[1] ISIS Pharmaceut, Dept Med Chem, Carlsbad, CA 92008 USA
[2] Merck Res Labs, Dept Biol Chem, West Point, PA 19486 USA
[3] Merck Res Labs, Dept Safety Assessment, West Point, PA 19486 USA
[4] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
关键词
D O I
10.1021/jm0495172
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Several triphosphates of modified nucleosides (1-6) were identified as inhibitors (IC50 = 0.083.8 muM) of hepatitis C virus RNA-dependent RNA polymerase (RdRp). Although the initial SAR developed by determining the ability of the triphosphates to inhibit the in vitro activity of the HCV RdRp identified several potent inhibitors, none of the corresponding nucleosides exhibited significant inhibitory potency in a cell-based replicon assay. To improve upon the activity, bis(tBu-S-acyl-2-thioethyl) nucleoside 5'-monophosphate esters (7-12) were synthesized, and these derivatives exhibited improved potency compared to the corresponding nucleosides in the cell-based assay. Analysis of the intracellular metabolism demonstrated that the S-acyl-2-thioethyl (SATE) prodrug is metabolized to the 5'-triphosphate 40- to 155-fold more efficiently compared to the corresponding nucleoside. The prodrug approach involving bis(tBuSATE)cytidine 5'-monophosphate ester significantly reduced the deamination of cytidine derivatives by cellular deaminases. Additionally, chromosomal aberration studies with the SATE prodrug in cells showed no statistically relevant increase in aberrations compared to the concurrent controls.
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收藏
页码:1199 / 1210
页数:12
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