Discovery of (<i>R</i>)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-<i>a</i>]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a Potent and Orally Available Hepatitis C Virus Polymerase Inhibitor

Li, Hui; Tatlock, John; Linton, Angelica; González, Javier; Jewell, Tanya; Patel, Leena; Ludlum, Sarah; Drowns, Matthew; Rahavendran, Sadayappan V.; Skor, Heather; Hunter, Robert N.; Shi, Stephanie T.; Herlihy, Koleen J.; Parge, Hans E.; Hickey, Michael J.; Xiang, Yu; Chau, Foo‐Tim; Nonomiya, Jim; Lewis, Cristina

doi:10.1021/jm8014537

Cited by 114 publications

(92 citation statements)

References 15 publications

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“…Filibuvir, also known as PF-00868554 (Fig. 1A), is a member of the dihydroxyprone class of compounds that was identified by a highthroughput screen and dihydroxyprone-based drug design efforts (26). Results from clinical phase 1b trial showed that filibuvir potently decreased viral RNA accumulation in a dose-dependent manner (http://clinicaltrials.gov/ct2/show/NCT00987337).…”

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confidence: 99%

Biochemical Study of the Comparative Inhibition of Hepatitis C Virus RNA Polymerase by VX-222 and Filibuvir

Deval²,

Fan

et al. 2012

Antimicrob Agents Chemother

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Filibuvir and VX-222 are nonnucleoside inhibitors (NNIs) that bind to the thumb II allosteric pocket of the hepatitis C virus (HCV) RNA-dependent RNA polymerase. Both compounds have shown significant promise in clinical trials and, therefore, it is relevant to better understand their mechanisms of inhibition. In our study, filibuvir and VX-222 inhibited the 1b/Con1 HCV subgenomic replicon, with 50% effective concentrations (EC 50 s) of 70 nM and 5 nM, respectively. Using several RNA templates in biochemical assays, we found that both compounds preferentially inhibited primer-dependent RNA synthesis but had either no or only modest effects on de novo-initiated RNA synthesis. Filibuvir and VX-222 bind to the HCV polymerase with dissociation constants of 29 and 17 nM, respectively. Three potential resistance mutations in the thumb II pocket were analyzed for effects on inhibition by the two compounds. The M423T substitution in the RNA polymerase was at least 100-fold more resistant to filibuvir in the subgenomic replicon and in the enzymatic assays. This resistance was the result of a 250-fold loss in the binding affinity (K d ) of the mutated enzyme to filibuvir. In contrast, the inhibitory activity of VX-222 was only modestly affected by the M423T substitution but more significantly affected by an I482L substitution. Hepatitis C virus (HCV), the major causative agent of non-A, non-B viral hepatitis, has been estimated to infect over 170 million people worldwide (12,24). Approximately 80% of the infected individuals will develop chronic infection, leading to liver cirrhosis and hepatocellular carcinoma (24). Two protease inhibitors have been recently approved by the FDA and can result in up to a 70% cure rate for genotype 1a-or 1b-infected patients when used in combination with pegylated alpha interferon and ribavirin (1, 17). However, resistance mutations to both ribavirin and the protease inhibitors have already been observed in patients, and there is a need to develop drugs to additional targets in HCV (3). The HCV-encoded NS5B, the RNA-dependent RNA polymerase (RdRp) (5), is a validated drug target, and intense efforts are focused on development of antiviral agents that inhibit its activities.The HCV RdRp can catalyze RNA synthesis in vitro by either a de novo-initiated mechanism or by extension from a primed template (19,40). These two modes of RNA synthesis have been used to classify the effects of HCV polymerase inhibitors (13). De novo initiation usually takes place by the base pairing of the initiating nucleoside triphosphate (NTP; usually a purine triphosphate) to the 3=-most nucleotide of the template RNA (usually a U or a C) (5,19,21,30). This mode of synthesis ensures that no genetic information from the viral genome is lost (18). It is the ratelimiting step in RNA synthesis and requires a higher K m of the initiating NTP (NTPi) than for the other nucleotides incorporated during elongation. Primer extension (PE) takes place when the 3= region of the template RNA loops back on itself to form a hairpin ...

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confidence: 99%

Biochemical Study of the Comparative Inhibition of Hepatitis C Virus RNA Polymerase by VX-222 and Filibuvir

Deval²,

Fan

et al. 2012

Antimicrob Agents Chemother

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“…The X-ray co-crystal structure of HCV NS5B-PF868554 (PDB ID: 3FRZ) obtained from the RCSB Protein Data Bank (Piscataway, NJ) was used for docking the compounds into the NS5B thumb pocket-II 22 . The protein structure was processed by means of default parameters mentioned in Protein Preparation Tool present in Maestro v9.0 and Impact program v5.5 (Schrödinger, Inc., New York, NY), in which the protonation states of residues were adjusted to the dominant ionic forms at pH 7.4.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…The resulting LigPrep derived structures were used for docking simulations. The X-ray co-crystal structure of HCV NS5B-PF868554 (PDB ID: 3FRZ) was used for docking into thumb pocket-II 22 . Protein refinement without crystallographic water molecules, energy grid generation using bound ligand as a reference, and ''Extra Precision'' (XP) Glide docking v5.0 (Schrödinger, Inc., New York, NY) was performed with the default parameters.…”

Section: Docking Protocolmentioning

confidence: 99%

“…Since the structurally related pyranoindoles have been previously shown to inhibit NS5B activity through binding to TP-II, we performed docking calculations at TP-II site 13,22 . Analysis of the binding energy data for the docked conformations of R-versus S-isomers of the most active compound of 5-[ (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, 4a (Glidescore for (R) ¼ À2.94 kcal/mol and for (S) ¼ À4.58 kcal/mol), showed that S-isomer bind at least by 1 kcal/mol better than their R-counterpart.…”

Section: Anti-hcv Ns5b Polymerase Activitymentioning

confidence: 99%

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Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles

Çıkla-Süzgün

Kaushik‐Basu

Basu

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Arachidonic acid is an unsaturated fatty acid liberated from phospholipids of cell membranes. NSAIDs are known as targets of cyclooxygenase enzyme (COX-1, COX-2 and COX-3) in arachidonic acid metabolism. This mechanism of COX-2 in carcinogenesis causes cancer. In addition, COX-2 plays a role in the early stages of hepatocarcinogenesis. Hepatitis C virus (HCV) infection is cause of liver cirrhosis and hepatocellular carcinoma (HCC). The aim of our study was to improve effective agents against HCV. A novel series of new etodolac 1,2,4-triazoles derivatives (4a-h) have been synthesized and investigated for their activity against HCV NS5B polymerase. Compound 4a was found to be the most active with IC 50 value of 14.8 mM. In accordance with these results, compound 4a was screened for anti-cancer activity on liver cancer cell lines (Huh7, Mahlavu, HepG2, FOCUS). Compound 4a showed anti-cancer activity against Huh7 human hepatoma cell line with IC 50 value of 4.29 mM. Therefore, compound 4a could be considered as a new anti-cancer and anti-HCV lead compound.

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“…Another natural compound was erysenegalensein C (Fig. 1) which has been extracted from the bark of Erythrina senegalensis and found probable use in the treatment of stomach pain, female infertility and gonorrhea 26 . manipulations.…”

Section: Introductionmentioning

confidence: 99%

Syntheses of Enaminone-Based Heterocyclic Compounds and Study their Biological Activity

Azab¹,

Break²,

El-Zahrani³

2016

Orient. J. Chem

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We herein reported the utility of 3-(3-(dimethylamino)acryloyl)-2H-chromen-2-one (2), as a versatile precursor for the synthesis of some new azole systems of possible biological activities. The structure of the newly synthesized compounds has been confirmed by IR, 1 H NMR, mass spectral and elemental analysis. Furthermore, some selected compounds were screened in vitro for their anti-microbial activities. The results declared that most of the synthesized compounds have high anti-microbial activity.

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Discovery of (R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a Potent and Orally Available Hepatitis C Virus Polymerase Inhibitor

Cited by 114 publications

References 15 publications

Biochemical Study of the Comparative Inhibition of Hepatitis C Virus RNA Polymerase by VX-222 and Filibuvir

Biochemical Study of the Comparative Inhibition of Hepatitis C Virus RNA Polymerase by VX-222 and Filibuvir

Anti-cancer and anti-hepatitis C virus NS5B polymerase activity of etodolac 1,2,4-triazoles

Syntheses of Enaminone-Based Heterocyclic Compounds and Study their Biological Activity

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