Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

Abstract

Background: With an increasing worldwide burden of liver failure and liver cancer from chronic hepatitis C virus (HCV) infection, discovery and development efforts for new antiviral medicines for HCV are expanding rapidly. Two HCV protease inhibitors (PIs), telaprevir (VX950) and boceprevir (SCH503034), are now furthest along in clinical development, with Phase II data suggesting a potential treatment advance with triple combination regimens comprising a protease inhibitor, pegylated interferon and ribavirin. However, the current data suggest that such regimens will fail to produce sustained virologic responses in ≥ 30 -40% of patients, and tolerance of interferon/ribavirin treatment regimens is often problematic; hence, there is a need for continued development of new anti-HCV agents to further optimize treatment efficacy and safety. The HCV polymerase (HCV Pol) is an attractive target for antiviral therapy because the gene sequences encoding HCV Pol are relatively conserved across the six main HCV genotypes and the emergence of viral resistance is expected to be relatively slow for pharmaceutical agents, such as nucleoside analogues, that are targeted to the active (catalytic) site of HCV Pol. Methods: This review (Part I) of HCV Pol inhibitors focuses on the scientific rationale and recent development progress for nucleoside-type HCV Pol inhibitors; a subsequent review (Part II) will assess progress with non-nucleosidic HCV Pol inhibitors. Results/conclusions: Early clinical data for several nucleosides targeted to HCV Pol indicate marked antiviral effects and a likelihood of relatively slow HCV resistance, consistent with the profile of nucleosidic inhibitors of HIV and hepatitis B virus infection and supporting potentially important roles for nucleoside agents in optimizing combination therapies for HCV infection. Optimally effective future anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase and PIs, together with pegylated interferon and ribavirin or pharmaceutical agents from other mechanistic classes.

Nucleoside and nucleotide analogues by catalyst free Huisgen nitrile oxide–alkyne1,3-dipolar cycloaddition

“…The LC/TOF-MS was a model 6210 Time-Of-Flight LC/MS (Agilent Corp, Santa Clara, CA) with an electrospray source positive and negative (ESI ±), capilary 3,500 V, nebuliser spray 30 psig, drying gas 5 L min -1 , source temperature 325 • C. The fragmentor was used at 175 V. Reference masses (Agilent solution) were 121.050873, 149.02332, 322.048121, 922.009798, 1221.990633, 1521.971475, and 2421.91399 m/z. The NMR spectra were obtained for 1 H at 300 MHz, for 13 C at 75 MHz and for 31 P at 121 MHz on a Bruker instrument at 25 • C. All samples for NMR were prepared in CDCl 3 . Chemical shifts are reported in ppm downfield from TMS as standard and coupling constants are reported in hertz.…”

“…[1][2][3][4] In parallel, the isoxazole ring has been identified as attractive in terms of its hydrolytic stability, its potential for p-stacking and H-bonding and due to its sharing the isosteric character of the amide and ester bond. 5, 6 It is well recognised that the activities of different segments within a molecule can act in concert or confer new attributes on the molecule, and in this context the synthesis and bioactivity of isoxazole, isoxazoline and isoxazolidine modified nucleosides has received much attention.…”

Overcoming Stability Challenges in the Quantification of Tissue Nucleotides: Determination of 2′-<i>C</i>-Methylguanosine Triphosphate Concentration in Mouse Liver

“…[8][9][10][11][12] For this class of compounds, the active entity is nucleoside triphosphate (NTP). The NTPs have poor cellular uptake and they undergo rapid enzymatic degradation.…”

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

“…Therefore, the combination of a non-nucleoside or protease inhibitor with a nucleoside polymerase inhibitor could have a clear clinical benefit through the delay of resistance emergence. Early clinical data for several nucleosides targeted to HCV RNA polymerase inhibitors indicated marked antiviral effects and a likelihood of relatively slow HCV resistance (Brown, 2009). Optimally effective anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase inhibitors and protease inhibitors together with PEG-IFN and RBV or pharmaceutical agents from other mechanistic classes.…”