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Antimicrobial Agents and Chemotherapy, January 2009, p. 186-192, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00333-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity{triangledown}

Makoto Yamashita,{dagger}* Takanori Tomozawa, Masayo Kakuta, Akane Tokumitsu, Hatsumi Nasu, and Shuku Kubo{dagger}

Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan

Received 11 March 2008/ Returned for modification 25 April 2008/ Accepted 10 October 2008

Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.

* Corresponding author. Mailing address: Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan. Phone: 81-3-3492-3131. Fax: 81-3-5436-8578. E-mail: yamashita.makoto.yr{at}daiichisankyo.co.jp

{triangledown} Published ahead of print on 27 October 2008.

{dagger} M.Y. and S.K. contributed equally to this study.

Antimicrobial Agents and Chemotherapy, January 2009, p. 186-192, Vol. 53, No. 1
0066-4804/09/$08.00+0     doi:10.1128/AAC.00333-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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