640725-73-1Relevant articles and documents
β-D-2′-C-methyl-2,6-diaminopurine ribonucleoside phosphoramidates are potent and selective inhibitors of hepatitis C virus (HCV) and are bioconverted intracellularly to bioactive 2,6-diaminopurine and guanosine 5′-triphosphate forms
Zhou, Longhu,Zhang, Hong-Wang,Tao, Sijia,Bassit, Leda,Whitaker, Tony,Mcbrayer, Tamara R.,Ehteshami, Maryam,Amiralaei, Sheida,Pradere, Ugo,Cho, Jong Hyun,Amblard, Franck,Bobeck, Drew,Detorio, Mervi,Coats, Steven J.,Schinazi, Raymond F.
, p. 3445 - 3458 (2015/05/05)
The conversion of selected β-d-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2′-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2′-C-Me-DAPN-TP and 2′-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2′-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 μM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.
Structure-Activity Relationship of Purine Ribonucleosides for Inhibition of Hepatitis C Virus RNA-Dependent RNA Polymerase
Eldrup, Anne B.,Allerson, Charles R.,Bennett, C. Frank,Bera, Sanjib,Bhat, Balkrishen,Bhat, Neelima,Bosserman, Michele R.,Brooks, Jennifer,Burlein, Christine,Carroll, Steven S.,Cook, P. Dan,Getty, Krista L.,MacCoss, Malcolm,McMasters, Daniel R.,Olsen, David B.,Prakash, Thazha P.,Prhavc, Marija,Song, Quanlai,Tomassini, Joanne E.,Xia, Jie
, p. 2283 - 2295 (2007/10/03)
As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2′-C-Methyladenosine and 2′-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure- activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2′- and 3′-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2′ -C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism.
