Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid

Stansfield, Ian; Avolio, Salvatore; Colarusso, Stefania; Gennari, Nadia; Narjes, Frank; Pacini, Barbara; Ponzi, Simona; Harper, Steven J.

doi:10.1016/j.bmcl.2004.07.075

Cited by 42 publications

(26 citation statements)

References 12 publications

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“…The N-terminal domain (approximately 180 amino acids) of NS3 and the small hydrophobic NS4A protein compose a heterodimeric enzyme catalyzing the posttranslational processing of the HCV NS proteins (1, 21). Both NS5B RdRp and NS3 serine protease are believed to be components of the HCV replication complex, responsible for viral RNA replication, and have been shown to be indispensable for HCV replication in chimpanzees (26).To date, a number of distinct classes of NS5B RdRp inhibitors, including nucleoside analogs, pyrophosphate mimics, and nonnucleoside analogs, have been reported in the scientific and patent literature (12,13,20,40,50,51). The nucleoside analogs act as chain terminators by competing with the substrate of RdRp (40).…”

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confidence: 99%

“…To date, a number of distinct classes of NS5B RdRp inhibitors, including nucleoside analogs, pyrophosphate mimics, and nonnucleoside analogs, have been reported in the scientific and patent literature (12,13,20,40,50,51). The nucleoside analogs act as chain terminators by competing with the substrate of RdRp (40).…”

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confidence: 99%

“…This class of compounds has been shown to inhibit HCV replication in both subgenomic replicons and HCV-infected chimpanzees (5,19,41,49). The pyrophosphate mimics, including dihydroxypyrimidine carboxylic acids and diketoacid derivatives, are believed to inhibit RdRp activity through an interaction with the catalytic metal ions in the enzyme active site (42,50,51). For nonnucleoside analogs, several structurally distinct series have been identified, including benzothiadiazines, benzimidazoles/diamides, substituted pyranones, and disubstituted phenylalanine/thiophene amides (13,22,25,33,47,52,57).…”

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confidence: 99%

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Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Pilot‐Matias

et al. 2005

Antimicrob Agents Chemother

121

112

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Compounds A-782759 (an N-1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific antihepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase and the NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture. In order to characterize the development of resistance to these anti-HCV agents, HCV subgenomic 1b-N replicon cells were cultured with A-782759 alone or in combination with BILN-2061 at concentrations 10 times above their corresponding 50% inhibitory concentrations in the presence of neomycin. Single substitutions in the NS5B polymerase gene (H95Q, N411S, M414L, M414T, or Y448H) resulted in substantial decreases in susceptibility to A-782759. Similarly, replicons containing mutations in the NS5B polymerase gene (M414L or M414T), together with single mutations in the NS3 protease gene (A156V or D168V), conferred high levels of resistance to both A-782759 and BILN-2061. However, the A-782759-resistant mutants remained susceptible to nucleoside and two other classes of nonnucleoside NS5B polymerase inhibitors, as well as interferon. In addition, we found that the frequency of replicons resistant to both compounds was significantly lower than the frequency of resistance to the single compound. Furthermore, the dually resistant mutants displayed significantly reduced replication capacities compared to the wild-type replicon. These findings provide strategic guidance for the future treatment of HCV infection.Hepatitis C virus (HCV) is a leading cause of chronic liver disease, affecting over 4 million Americans and about 170 million people worldwide. The current standard of care for chronic HCV infection involves extended dosing with alpha interferon (IFN-␣) and ribavirin (10,14,18). However, these regimens have limited clinical benefit due to poor tolerability and limited efficacy (only approximately half of genotype 1 HCV-infected individuals have a sustained virological response, whereas the response rate improves significantly [ϳ80%] when genotypes 2 and 3 are treated) (9,11,35). Therefore, development of inhibitors against virally encoded targets is urgently needed.The HCV genome is a 9.6-kb single-stranded RNA of positive polarity encoding a large polyprotein, which is the precursor of at least 10 mature viral proteins: C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (2). The HCV polymerase encoded by nonstructural protein 5B (NS5B) is responsible for HCV RNA-dependent RNA polymerase (RdRp) and terminal transferase activities (4,31,32). The N-terminal domain (approximately 180 amino acids) of NS3 and the small hydrophobic NS4A protein compose a heterodimeric enzyme catalyzing the posttranslational processing of the HCV NS proteins (1, 21). Both NS5B RdRp and NS3 serine protease are believed to be components of the HCV replication complex, responsible for viral RNA replication, and have been shown to be indispensable for HCV replication in chimpanzees (26).To date, a number of distinct classes of NS5B RdRp inhibitors...

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Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Pilot‐Matias

et al. 2005

Antimicrob Agents Chemother

121

112

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“…That pyrimidone B is an inhibitor was shown by N-methylation (R = Me) which gave an equally active pyrimidone. 22 1. 5,6-Dihydroxypyrimidine-4-carboxylic acids…”

Section: Figurementioning

confidence: 99%

“…As the structures in Figure 4 show, this was not successful, except in the case of the N-methylpyrimidone 27 and the pyridine-N-oxide 28, which showed similar potency with respect to the parent dihydroxypyrimidines 13 and 3. 22,27 The initial synthesis for 27 and 28 did not allow the introduction of a wide variety of substituents, and thus limited a full exploration of the SAR. To overcome these limitations we investigated several possible routes towards these novel ketoacid replacements.…”

Section: Investigation Of the Dihydroxypyrimidine Corementioning

confidence: 99%

Inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

Attenni¹,

Avolio²,

Colarusso³

et al. 2006

Arkivoc

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Infections caused by Hepatitis C Virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed diketoacids 1 and dihydroxypyrimidine carboxylates 3 as novel, reversible inhibitors of the HCV NS5B polymerase. We report here the further development of 3 into the more potent 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids. The structure activity relationship of these inhibitors is discussed in the context of their physicochemical properties, supporting the proposed binding model, which involves pyrophosphate like chelation of the active site Mg-ions. We also report on the discovery and synthesis of two related scaffolds, the N1-substituted pyrimidones and pyridine-N-oxides.

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HIV Integrase Inhibitor: Raltegravir

Humphrey¹,

Zhong

2010

The Art of Process Chemistry

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Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid

Cited by 42 publications

References 12 publications

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

HIV Integrase Inhibitor: Raltegravir

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