کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10588200 | 981449 | 2012 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
β-d-2â²-α-F-2â²-β-C-Methyl-6-O-substituted 3â²,5â²-cyclic phosphate nucleotide prodrugs as inhibitors of hepatitis C virus replication: A structure-activity relationship study
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 18, 15 September 2012, Pages 5924-5929
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 18, 15 September 2012, Pages 5924-5929
نویسندگان
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,