Synthesis and evaluation of novel phosphoramidate prodrugs of 2'-methyl cytidine as inhibitors of hepatitis C virus NS5B polymerase.
A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieved.
Donghi
Monica
M
Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina Km 30,600, 00040 Pomezia (Rome), Italy.
Attenni
Barbara
B
Gardelli
Cristina
C
Marco
Annalise Di
AD
Fiore
Fabrizio
F
Giuliano
Claudio
C
Laufer
Ralph
R
Leone
Joseph F
JF
Pucci
Vincenzo
V
Rowley
Michael
M
Narjes
Frank
F
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D006801:Humans; D010756:Phosphoric Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D010756:Phosphoric Acids; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C513402:2'-C-methylcytidine; D003562:Cytidine; C011067:phosphoramidic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase