title: Liver-targeted prodrugs of 2'-C-methyladenosine for therapy of hepatitis C virus infection.
abstract: 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%.
authors.affiliation: Departments of Biochemistry and Medicinal Chemistry, Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, CA 92037, USA. hecker@mbasis.com
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hecker
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Poelje
authors.forename: Zhili
authors.initials: Z
authors.lastname: Sun
authors.forename: Wenjian
authors.initials: W
authors.lastname: Huang
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Varkhedkar
authors.forename: M Venkat
authors.initials: MV
authors.lastname: Reddy
authors.forename: James M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Koeplinger
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.forename: David L
authors.initials: DL
authors.lastname: Linemeyer
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D006526:Hepatitis C / Q000188:drug therapy*; D022781:Hepatocytes / Q000378:metabolism; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010755:Organophosphates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D010755:Organophosphates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C024341:2'-O-methyladenosine; D000241:Adenosine