Liver-Targeted Prodrugs of 2‘-<i>C</i>-Methyladenosine for Therapy of Hepatitis C Virus Infection

Hecker, Scott J.; Reddy, K. Rajender; Poelje, Paul D. van; Sun, Zhili; Huang, Wenjian; Varkhedkar, Vaibhav; Reddy, M. Venkat Ram; Fujitaki, James M.; Olsen, David B.; Koeplinger, Kenneth A.; Boyer, Serge H.; Linemeyer, David L.; MacCoss, Malcolm; Erion, Mark D.

doi:10.1021/jm0701021

Cited by 34 publications

(24 citation statements)

References 17 publications

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“…Finally, it was found that the use of t- BuMgCl on 2′,3′-protected nucleosides resulted in the exclusive formation of cis -isomers as illustrated in Scheme 70 with cytarabine (52%) 99 and 2′-Me-A (35%). 101 Determination of the stereochemistry of the final product was established by comparison of NMR data with literature examples. Isopropylidene and TBS protective groups were finally removed after phosphorylation under acidic condition or by treatment with a source of fluorine (TEAF, TBAF).…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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“…There was a substantial increase in mice, compared to the non-phosphorylated AraC as a control. The HepDirect technology also was applied to a 2′,3′-carbonate to make an orally available compound (39%) with high liver potency [81,82]. …”

Section: Ester Prodrugsmentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

153

135

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A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

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“…Since it was hypothesized that preparation of a 5′-monophosphate prodrug would block deamination and increase therapeutic levels of 2′-C-methyladenosine triphosphate (10) in the liver, a HepDirect prodrug approach was investigated. An SAR study evaluated activation in rat hepatocytes by modifications to the aryl substituent of the HepDirect prodrug moiety [108]. This assessment showed that the prodrugs were generally efficiently cleaved and converted to the nucleoside triphosphate 10 ( Figure 6) particularly those with halogen substituted phenyl 51 or pyridyl groups ( Figure 19).…”

Section: ′-C-methyladenosine Hepdirect Prodrugsmentioning

confidence: 99%

Nucleotide Prodrugs for HCV Therapy

Sofia¹

2011

Antivir Chem Chemother

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HCV infection is a significant worldwide health problem and is a major cause of hepatocellular carcinoma. The current standard of care, interferon and ribavirin, is only effective against a proportion of the patient population infected with HCV. To address the shortcomings of existing therapy, the development of direct acting antiviral agents is under investigation. The HCV RNA dependent RNA polymerase is an essential enzyme for viral replication and is therefore a logical target against which to develop novel anti-HCV agents. Nucleosides have been shown to be effective as antiviral agents for other viral diseases and therefore, have been investigated as inhibitors of HCV replication. The development of prodrugs of nucleoside 5'-monophosphates has been pursued to address limitations associated with poor nucleoside phosphorylation. This is required to produce the nucleoside 5'-triphosphate which is the anabolite that is the actual inhibitor of the polymerase enzyme. Prodrugs of nucleoside 5'-monophosphates have been developed that enable their delivery into cells and in vivo into the liver. The implementation of these prodrug strategies has ultimately led to the identification of several prodrugs of nucleoside 5'-monophosphates that are potent inhibitors of HCV replication in vitro. They have progressed into the clinic and the early data demonstrate greatly reduced viral load levels in HCV-infected patients. This review will survey the state of nucleotide prodrugs for the treatment of HCV.

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

Cited by 34 publications

References 17 publications

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Nucleotide Prodrugs for HCV Therapy

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