Liver-Targeted Prodrugs of 2‘-C-Methyladenosine for Therapy of Hepatitis C Virus Infection

• Published in: Journal of medicinal chemistry Vol. 50; no. 16; pp. 3891 - 3896
• Main Authors: Hecker, Scott J, Reddy, K. Raja, van Poelje, Paul D, Sun, Zhili, Huang, Wenjian, Varkhedkar, Vaibhav, Reddy, M. Venkat, Fujitaki, James M, Olsen, David B, Koeplinger, Kenneth A, Boyer, Serge H, Linemeyer, David L, MacCoss, Malcolm, Erion, Mark D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.08.2007; Amer Chemical Soc
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - pharmacokinetics; Adenosine - pharmacology; Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Biological and medical sciences; Biological Availability; Chemistry, Medicinal; Hepatitis C - drug therapy; Hepatitis C virus; Hepatocytes - metabolism; Injections, Intravenous; Life Sciences & Biomedicine; Liver - drug effects; Liver - metabolism; Medical sciences; Organophosphates - chemical synthesis; Organophosphates - pharmacokinetics; Organophosphates - pharmacology; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - pharmacokinetics; Organophosphorus Compounds - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphorylation; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; PARAOXONASE; DESIGN; DEPENDENT RNA-POLYMERASE; REPLICATION; INHIBITION; NUCLEOSIDE ANALOGS; LACTONES; RIBONUCLEOSIDES; PARENCHYMAL-CELLS; Biological fluid; Intravenous administration; Rat; Liver; Oxygen phosphorus heterocycle; Branched compound; Blood; Pyridine derivatives; Hepatocyte; Structure activity relation; Six membered ring; Targeted drug; Antiviral; Chemical synthesis; Ribonucleotide; Purine nucleotide; Rodentia; Oral administration; Bioavailability; Prodrug; In vitro; Virus; In vivo; Hydrolysis resistance; Vertebrata; Mammalia; Animal; Flaviviridae; Pharmacokinetics; Hepatitis C virus; Hepacivirus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0701021

2‘-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2‘,3‘-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2‘,3‘-carbonate moiety displayed oral bioavailability of 39%.