Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en

Honda, Takeshi; Kubo, Shuku; Masuda, Takeshi; Arai, Masami; Kobayashi, Yoshiyuki; Yamashita, Makoto

doi:10.1016/j.bmcl.2009.04.067

Cited by 45 publications

(27 citation statements)

References 20 publications

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“…We found a new strong neuraminidase inhibitor, laninamivir (code name, R-125489), and reported that CS-8958 (laninamivir octanoate or the laninamivir prodrug) worked as a longacting neuraminidase inhibitor (12,16,23). Laninamivir potently inhibited the neuraminidase activities of various influenza A and B viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses (23), as well as pandemic 2009 H1N1 virus (14).…”

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confidence: 99%

Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Kubo

Tomozawa

Kakuta

et al. 2010

Antimicrob Agents Chemother

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119

103

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Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for use for the treatment and prophylaxis of influenza. We have reported on laninamivir (code name, R-125489), a novel neuraminidase inhibitor, and have discovered that the laninamivir prodrug CS-8958 worked as a long-acting neuraminidase inhibitor in a mouse influenza virus infection model when it is intranasally administered. In this study, CS-8958 was administered just once 7 days before infection and showed significant efficacy in vivo. The efficacy of a single administration of CS-8958 after viral infection was then compared with that of repeated administrations of oseltamivir phosphate or zanamivir in mice and ferrets. CS-8958 showed efficacy superior or similar to the efficacies of the two licensed NA inhibitors. CS-8958 also significantly reduced the titers of an oseltamivir-resistant H1N1 virus with a neuraminidase H274Y substitution in a mouse infection model. These results suggest that since CS-8958 is characteristically long lasting in the lungs, it may be ideal for the prophylaxis and treatment of influenza.

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mentioning

confidence: 99%

Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Kubo

Tomozawa

Kakuta

et al. 2010

Antimicrob Agents Chemother

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119

103

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“…Recently, Honda et al reported that 7-O-methyl- Neu5Ac2en derivative (7a) and 7-O-methyl-9-O-octanoylNeu5Ac2en sialidase inhibitor (7b), carrying a 4-guanidinoNeu5Ac2en framework, inhibited influenza virus replication much more effectively than zanamivir did (9) (Fig. 4).…”

Section: B Analogs Of 2-deoxy-23-didehydro Sialic Acidsmentioning

confidence: 96%

Sialic Acid Derivative Synthesis and Inhibitory Activities against Human Parainfluenza Virus Type 1

Ikeda

2011

TIGG

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“…1), which shows potent neuraminidase inhibitory activities in vitro against various influenza A and B viruses, including oseltamivirresistant viruses , 2009 pandemic H1N1 viruses (Itoh et al, 2009), and highly pathogenic H5N1 influenza viruses (Kiso et al, 2010). In a mouse influenza virus A/Puerto Rico/ 8/34 infection model, the intranasal dose of laninamivir demonstrated a prolonged survival effect, and this effect was drastically improved by derivatization into the octanoyl ester prodrug LO Honda et al, 2009). In the same model, a single intranasal dose of LO showed an antiviral effect that is similar to that after the repeated intranasal dose of zanamivir and superior to that after the repeated oral dose of oseltamivir .…”

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confidence: 99%

Pharmacokinetic Mechanism Involved in the Prolonged High Retention of Laninamivir in Mouse Respiratory Tissues after Intranasal Administration of its Prodrug Laninamivir Octanoate

et al. 2012

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Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 mmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using 14 C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 mM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h 21, which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery.

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Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en

Cited by 45 publications

References 20 publications

Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Laninamivir Prodrug CS-8958, a Long-Acting Neuraminidase Inhibitor, Shows Superior Anti-Influenza Virus Activity after a Single Administration

Sialic Acid Derivative Synthesis and Inhibitory Activities against Human Parainfluenza Virus Type 1

Pharmacokinetic Mechanism Involved in the Prolonged High Retention of Laninamivir in Mouse Respiratory Tissues after Intranasal Administration of its Prodrug Laninamivir Octanoate

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