Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10588200 | Bioorganic & Medicinal Chemistry Letters | 2012 | 6 Pages |
Abstract
The 3â²,5â²-cyclic phosphate prodrug 9-[β-d-2â²-deoxy-2â²-α-fluoro-2â²-β-C-methylribofuranosyl]-2-amino-6-ethoxypurine, PSI-352938 1, has demonstrated promising anti-HCV efficacy in vitro and in human clinical trials. A structure-activity relationship study of the nucleoside 3â²,5â²-cyclic phosphate series of β-d-2â²-deoxy-2â²-α-fluoro-2â²-β-C-methylribofuranosyl nucleoside prodrugs was undertaken and the anti-HCV activity and in vitro safety profile were assessed. Cycloalkyl 3â²,5â²-cyclic phosphate prodrugs were shown to be significantly more potent as inhibitors of HCV replication than branched and straight chain alkyl 3â²,5â²-cyclic phosphate prodrugs. No cytotoxicity and mitochondrial toxicity for prodrugs 12, 13 and 19 were observed at concentrations up to 100 μm in vitro. Cycloalkyl esters of 3â²,5â²-cyclic phosphate nucleotide prodrugs demonstrated the ability to produce high levels of active triphosphate in clone-A cells and primary human hepatocytes. Compounds 12, 13 and 19 also demonstrated the ability to effectively deliver in vivo high levels of active nucleoside phosphates to rat liver.
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Authors
Jinfa Du, Donghui Bao, Byoung-Kwon Chun, Ying Jiang, P. Ganapati Reddy, Hai-Ren Zhang, Bruce S. Ross, Shalini Bansal, Haiying Bao, Christine Espiritu, Angela M. Lam, Eisuke Murakami, Congrong Niu, Holly M. Micolochick Steuer, Phillip A. Furman,