Use of 2′-Spirocyclic Ethers in HCV Nucleoside Design

Du, Jinfa; Chun, Byoung-Kwon; Mosley, Ralph T.; Bansal, Shalini; Bao, Haiying; Espiritu, Christine; Lam, Angela M.; Murakami, Eisuke; Niu, Congrong; Steuer, Holly M. Micolochick; Furman, Phillip A.; Sofia, Michael J.

doi:10.1021/jm401224y

Cited by 39 publications

(27 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The discovery of HIV stimulated tremendous efforts in this regard [59], and the continued importance of the disease encourages continued efforts in this area, including use of prodrugs such as tenofovir disoproxil as preventative agents [175]. Furthermore, increasing concern for viral infections such as HCV [100,135,176,177] and herpes virus [56] also motivates research. Because there are numerous reviews focused on prodrugs of nucleotides and nucleoside phosphonates [178–184], the following paragraphs focus primarily on other emerging applications in the nucleotide area.…”

Section: Current Applications Of Prodrug Technologymentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

147

135

View full text Add to dashboard Cite

A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

show abstract

Section: Current Applications Of Prodrug Technologymentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

147

135

View full text Add to dashboard Cite

show abstract

“…13 A 2′-spiroetheruridine analogue (2, EC 50 = 14.9 μM, Figure 1) and its phosphoramidate prodrug (3, EC 50 = 20.6 μM, Figure 1) exhibited medium activity against HCV. 14 This may suggest that the 2′-α-C-alkyl in nucleosides/ nucleotides might be tolerated and that the 2′-α-OH or 2′-α-F may not be essential for nucleosides/nucleotides to exhibit anti-HCV activity. Sofosbuvir, with the modification of 2′-β-C-CH 3 -2′-α-C-F, shows potent activity against HCV, with few adverse effects.…”

mentioning

confidence: 99%

Discovery of 2′-α-C-Methyl-2′-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus

Zeng

Zhang

Nie

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

2′-α-C-Methyl-2′-β-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure− activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC 50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 μM, respectively. The docking study revealed that the recognition of the 2′-β-F by Arg158, 3′-OH by N291, and the Watson−Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain. KEYWORDS: hepatitis C virus, phosphoramidate prodrugs, docking, inhibitor, Hint 1 H epatitis C virus (HCV) is a small, single-stranded positive-sense RNA virus that was explicitly identified in 1989. 1 The 9.6 kb RNA genome shares similarities with the genomes of flaviviruses and pestiviruses. 2 HCV infection is a global health problem that impacts approximately 180 million individuals, of which approximately 150 million people may proceed to develop chronic liver disease. A significant percentage of patients may ultimately progress to liver cirrhosis and eventually develop hepatocellular carcinoma. 3 HCV infection is also the primary reason for liver transplants among adults. The therapy for HCV infection has long been regular injections of pegylated α-interferon with the daily oral administration of ribavirin (RBV). 4 This standard of care (SOC) functions by enhancing the host immune system rather than acting directly on the virus. However, HCV patients undergoing this therapy may also suffer significant adverse effects, including fatigue, hemolytic anemia, depression, and flulike symptoms, which are poorly tolerated. In 2011, boceprevir and telaprevir, as HCV protease inhibitors, became available to treat HCV infection with genotype 1 in combination with ribavirin and pegylated interferon. 5 In 2013, two new directacting antivirals (DAAs), simeprevir and sofosbuvir, were approved by the FDA, which significantly enhanced the available armory. 6 However, the high cost for a course of treatment with sofosbuvir creates a considerable economic burden for patients. 7 Hence, the search for novel DAAs that are safe and effective remains a necessary endeavor.The HCV NS5B RNA-dependent RNA polymerase is a key enzyme in the replication of the virus. Therefore, it has become an attractive target for the development of small molecule inhibitors of viral replication. Nucleoside and nucleotide inhibitors of HCV (NIs) are a class of DAAs that show broad activity across HCV genotypes and a high barrier to the emergence of viral resistance. 8 Structural modifications have been made to both the base and ribose sugar portions of a ribonucleoside to develop potent and selective anti-HCV inhibitors. 9 Structural modifications of the ribose sugar portion focused primarily on the 1′-, 2′-, and 4′-positions. Structural modifications of the 2′-position mainly consisted of introducing an alkyl or including a methyl at the β-position ...

show abstract

“…15,16 They were complemented with the spirocyclic 2'-deoxy-2'-spirocyclopropyl and the 2'-deoxy-2'-spirooxetane moeity. 17,18,19 Recently, the 2'-α-fluoro-2'-β-chloro derivative was also reported 20 ( Figure 1). These 2'-variants not only need to mimic the interaction between the polymerase and the 2'-α-OH group present in natural ribonucleotides, they also must conform to the steric limitations of the corresponding 2'-region of the polymerase to result in proper inhibition thereof.…”

Section: Introductionmentioning

confidence: 93%

Discovery of 1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2′-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3′-5′-Cyclic Phosphate Ester Prodrug of 2′-Deoxy-2′-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition

et al. 2016

View full text Add to dashboard Cite

JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype (GT) 1b replicon-containing cell line 9 is devoid of any anti-HCV activity, an observation attributable to inefficient prodrug metabolism which was found to be CYP3A4-dependent. In contrast, in vitro incubation of 9 in primary human hepatocytes as well as pharmacokinetic evaluation thereof in different preclinical species reveals the formation of substantial levels of 2'-deoxy-2'-spirooxetane uridine triphosphate (8), a potent inhibitor of the HCV NS5B polymerase. Overall, it was found that 9 displays a superior profile compared to its phosphoramidate prodrug analogues (e.g., 4) described previously. Of particular interest is the in vivo dose dependent reduction of HCV RNA observed in HCV infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days of oral administration of 9.

show abstract

Use of 2′-Spirocyclic Ethers in HCV Nucleoside Design

Cited by 39 publications

References 24 publications

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Discovery of 2′-α-C-Methyl-2′-β-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus

Discovery of 1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2′-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3′-5′-Cyclic Phosphate Ester Prodrug of 2′-Deoxy-2′-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition

Contact Info

Product

Resources

About