Synthesis and antiviral properties of novel tetracyclic nucleoside inhibitors of hepatitis C NS5B polymerase.
As part of an ongoing medicinal chemistry effort to identify novel nucleoside inhibitors of HCV NS5B polymerase, we report the discovery of a novel series of 2'-C-Methyl-ribose nucleoside derivatives bearing a 7-aryl and 7-heteroaryl- substituted 7-deaza-adenine nucleobase. A reliable platform for the synthesis and simplified purification of the corresponding nucleoside triphosphates (NTPs) was established, enabling a solid understanding of the SAR relationship within the series. By this approach, we identified the novel analogs 13a and 13b that demonstrated micromolar levels of cellular activity, and the NTPs of which, 16a and 16b, are excellent inhibitors of NS5B with IC(50) = 0.1 μM, a level of intrinsic potency similar to that of previous and current clinical candidates.
Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, Pomezia, Italy. medifrancesco@mdanderson.org
M Emilia
ME
Di Francesco
Salvatore
S
Avolio
Gabriella
G
Dessole
Uwe
U
Koch
Marco
M
Pompei
Vincenzo
V
Pucci
Michael
M
Rowley
Vincenzo
V
Summa
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D009705:Nucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase