R-1479 - CAS 478182-28-4
Catalog number: 478182-28-4
Category: Inhibitor
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Molecular Formula:
C9H12N6O5
Molecular Weight:
284.23
COA:
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Targets:
HCV
Description:
R1479 is a potent and highly specific inhibitor of HCV replication in cell culture, and that its triphosphate is a potent and highly selective inhibitor of NS5B mediated RNA synthesis, the HCV encoded RNA polymerase.
Purity:
>98%
Synonyms:
4'-Azidocytidine
MSDS:
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InChIKey:
ODLGMSQBFONGNG-JVZYCSMKSA-N
InChI:
InChI=1S/C9H12N6O5/c10-4-1-2-15(8(19)12-4)7-5(17)6(18)9(3-16,20-7)13-14-11/h1-2,5-7,16-18H,3H2,(H2,10,12,19)/t5-,6+,7-,9-/m1/s1
Canonical SMILES:
C1=CN(C(=O)N=C1N)C2C(C(C(O2)(CO)N=[N+]=[N-])O)O
1.The design, synthesis, and antiviral activity of 4'-azidocytidine analogues against hepatitis C virus replication: the discovery of 4'-azidoarabinocytidine.
Smith DB;Kalayanov G;Sund C;Winqvist A;Pinho P;Maltseva T;Morisson V;Leveque V;Rajyaguru S;Le Pogam S;Najera I;Benkestock K;Zhou XX;Maag H;Cammack N;Martin JA;Swallow S;Johansson NG;Klumpp K;Smith M J Med Chem. 2009 Jan 8;52(1):219-23. doi: 10.1021/jm800981y.
4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.
2.R-1626, a specific oral NS5B polymerase inhibitor of hepatitis C virus.
Toniutto P;Fabris C;Bitetto D;Fumolo E;Fornasiere E;Pirisi M IDrugs. 2008 Oct;11(10):738-49.
Roche Holding AG is developing R-1626, an oral nucleoside inhibitor of HCV RNA polymerase. R-1626 has been demonstrated to be well absorbed and rapidly converted to the active component R-1479. The compound has demonstrated a strong capacity to inhibit HCV replication in vitro and in vivo, without the rapid development of viral resistance. After 4 weeks of treatment with R-1626 in combination with PEG-IFN plus ribavirin in treatment-naïve patients with genotype 1 HCV infection, HCV RNA could no longer be detected in approximately 74% of patients, compared with 5% of patients treated with PEG-IFN plus ribavirin alone, indicating the high potency of R-1626 to induce HCV RNA viral load reductions. R-1626 was generally well tolerated, although severe side effects of neutropenia were observed at high doses. A phase IIb clinical trial was ongoing at the time of publication to test the efficacy of R-1626 in combination with a standard or lower dose of PEG-IFN and ribavirin in HCV genotype 1-infected patients. Given its potent antiviral effect with an apparent high genetic barrier, R-1626 represents an important advancement in improving the outcome of patients with chronic HCV infection.
3.Structure-activity relationship analysis of mitochondrial toxicity caused by antiviral ribonucleoside analogs.
Jin Z;Kinkade A;Behera I;Chaudhuri S;Tucker K;Dyatkina N;Rajwanshi VK;Wang G;Jekle A;Smith DB;Beigelman L;Symons JA;Deval J Antiviral Res. 2017 Jul;143:151-161. doi: 10.1016/j.antiviral.2017.04.005. Epub 2017 Apr 12.
Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some have hypothesized that the active metabolites of toxic ribonucleoside analogs, the triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting mitochondrial RNA transcription and protein synthesis. Others have proposed that the prodrug moiety released from the ribonucleoside analogs might instead cause toxicity. Here, we report the mitochondrial effects of several clinically relevant and structurally diverse ribonucleoside analogs including NITD-008, T-705 (favipiravir), R1479 (parent nucleoside of balapiravir), PSI-7851 (sofosbuvir), and INX-08189 (BMS-986094). We found that efficient substrates and chain terminators of POLRMT, such as the nucleoside triphosphate forms of R1479, NITD-008, and INX-08189, are likely to cause mitochondrial toxicity in cells, while weaker chain terminators and inhibitors of POLRMT such as T-705 ribonucleoside triphosphate do not elicit strong in vitro mitochondrial effects. Within a fixed 3'-deoxy or 2'-C-methyl ribose scaffold, changing the base moiety of nucleotides did not strongly affect their inhibition constant (K;i;) against POLRMT.
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CAS 478182-28-4 R-1479

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