Discovery of 4′-azido-2′-deoxy-2′-C-methyl cytidine and prodrugs thereof: A potent inhibitor of Hepatitis C virus replication

Nilsson, Magnus; Kalayanov, G. D.; Winqvist, Anna; Pinho, Pedro; Sund, Christian; Zhou, Xiao Xiong; Wähling, Horst; Belfrage, Anna Karin; Pelcman, Michael; Agback, Tatiana; Benckestock, Kurt; Wikström, Kristina; Boothee, Mirva; Lindqvist, Anneli; Rydegård, Christina; Jonckers, Tim H. M.; Vandyck, Koen; Raboisson, Pierre; Lin, Tse‐I; Lachau‐Durand, Sophie; Kock, Herman de; Smith, David B.; Martin, Joseph A.; Klumpp, Klaus; Simmen, Kenneth; Vrang, Lotta; Terelius, Ylva; Samuelsson, Bertil; Rosenquist, Åsa; Johansson, Nils Gunnar

doi:10.1016/j.bmcl.2012.03.021

Cited by 17 publications

(12 citation statements)

References 20 publications

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“…85 Other interesting compounds, 4′-azido-2′-deoxy-2′- C -methylcytidine and its ester prodrugs, were found to show nano- or low micromolar antiviral efficacy in vitro. 86 Unfortunately, such nucleoside scaffolds have not been evaluated against arthropod-borne flaviviruses; the reported results originate from HCV replicon-based assays. 85 , 86 …”

Section: Inhibitors Of Flaviviral Ns5 Rdrpmentioning

confidence: 99%

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Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses

Eyer

Nencka

Clercq

et al. 2018

Antivir Chem Chemother

118

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Nucleoside analogs represent the largest class of small molecule-based antivirals, which currently form the backbone of chemotherapy of chronic infections caused by HIV, hepatitis B or C viruses, and herpes viruses. High antiviral potency and favorable pharmacokinetics parameters make some nucleoside analogs suitable also for the treatment of acute infections caused by other medically important RNA and DNA viruses. This review summarizes available information on antiviral research of nucleoside analogs against arthropod-borne members of the genus Flavivirus within the family Flaviviridae, being primarily focused on description of nucleoside inhibitors of flaviviral RNA-dependent RNA polymerase, methyltransferase, and helicase/NTPase. Inhibitors of intracellular nucleoside synthesis and newly discovered nucleoside derivatives with high antiflavivirus potency, whose modes of action are currently not completely understood, have drawn attention. Moreover, this review highlights important challenges and complications in nucleoside analog development and suggests possible strategies to overcome these limitations.

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Section: Inhibitors Of Flaviviral Ns5 Rdrpmentioning

confidence: 99%

“… 86 Unfortunately, such nucleoside scaffolds have not been evaluated against arthropod-borne flaviviruses; the reported results originate from HCV replicon-based assays. 85 , 86 …”

Section: Inhibitors Of Flaviviral Ns5 Rdrpmentioning

confidence: 99%

Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses

Eyer

Nencka

Clercq

et al. 2018

Antivir Chem Chemother

118

View full text Add to dashboard Cite

show abstract

“…Under the agreement, Medivir and Tibotec jointly performed preclinical studies to identify potential compounds. As an effort to explore 4′-azido-2′-modified cytidines as potential HCV polymerase inhibitors known for their antiviral HCV activities, Medivir’s scientists designed and synthesized 4′-azido-2′-deoxy-2′-methyl-cytidine 33 (Nilsson et al, 2012) (Fig. 13), which exhibited a moderate anti-HCV activity (Johansson et al, 2008).…”

Section: Tmc649128mentioning

confidence: 99%

Chutes and ladders in hepatitis C nucleoside drug development

et al. 2014

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Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.

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“…76 The 3 0 ,5 0 -diisobutryate ester prodrug TMC649128 (78) was subsequently identified as a clinical development candidate with 65% oral bioavailability when dosed in rats. 76 The 3 0 ,5 0 -diisobutryate ester prodrug TMC649128 (78) was subsequently identified as a clinical development candidate with 65% oral bioavailability when dosed in rats.…”

Section: Hepatitis C Virusmentioning

confidence: 99%

Nucleosides and Nucleotides for the Treatment of Viral Diseases

Sofia¹

2014

Annual Reports in Medicinal Chemistry

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Discovery of 4′-azido-2′-deoxy-2′-C-methyl cytidine and prodrugs thereof: A potent inhibitor of Hepatitis C virus replication

Cited by 17 publications

References 20 publications

Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses

Nucleoside analogs as a rich source of antiviral agents active against arthropod-borne flaviviruses

Chutes and ladders in hepatitis C nucleoside drug development

Nucleosides and Nucleotides for the Treatment of Viral Diseases

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