Synthesis and evaluation of S-acyl-2-thioethyl esters of modified nucleoside 5'-monophosphates as inhibitors of hepatitis C virus RNA replication.
Several triphosphates of modified nucleosides (1-6) were identified as inhibitors (IC(50) = 0.08-3.8 microM) 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.
Prakash
Thazha P
TP
Department of Medicinal Chemistry, ISIS Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, California 92008, USA. tprakash@isisph.com
Prhavc
Marija
M
Eldrup
Anne B
AB
Cook
P Dan
PD
Carroll
Steven S
SS
Olsen
David B
DB
Stahlhut
Mark W
MW
Tomassini
Joanne E
JE
MacCoss
Malcolm
M
Galloway
Sheila M
SM
Hilliard
Catherine
C
Bhat
Balkrishen
B
D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000139:chemically induced; D006224:Cricetinae; D003412:Cricetulus; D003562:Cytidine / Q000031:analogs & derivatives* / Q000737:chemistry*; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D014316:Tritium; D017361:Viral Nonstructural Proteins / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
C498572:2'-O-methylcytidine 5'-(bis(S-pivaloyl-2-thioethyl)phosphate); D010755:Organophosphates; D011355:Prodrugs; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D014316:Tritium; C052203:2'-O-methylcytidine; D003562:Cytidine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D003568:Cytidine Monophosphate