CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity

Abstract

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.

FIG. 1.

Chemical structures of R-125489 and CS-8958.

FIG. 2.

In vivo efficacy of CS-8958 and R-125489 in a mouse influenza virus infection model. Influenza A virus A/PR/8/34-infected (500 PFU, 0 h) mice were given 0.2 μmol/kg of CS-8958 (filled squares), R-125489 (open squares), zanamivir (filled circles), and saline (open circles) at 4 h before infection and 4 h and 18 h p.i. The dose of 0.2 μmol/kg corresponded to 95, 69, and 66 μg/kg for CS-8958, R-125489, and zanamivir, respectively. The number of surviving mice was monitored for 20 days p.i. (n = 10). (Results were not significant for the R-125489 administration group versus the zanamivir administration group [P = 0.0732; log rank test]).

FIG. 3.

In vivo efficacy of the prodrug of R-125489 with acyl chains of various lengths in a mouse influenza virus infection model. Influenza A virus A/PR/8/34-infected (1,500 PFU, 0 h) mice given 0.3 μmol/kg of R-125489-C₈ (CS-8958, filled squares), R-125489-C₁₀ (filled triangles), R-125489-C₆ (open triangles), R-125489-C₄ (open squares), zanamivir (filled circles), and saline (open circles) (a) or R-125489-C₈ (CS-8958, filled squares), R-125489-C₁₀ (filled triangles), R-125489-C₁₄ (open triangles), R-125489-C₁₆ (open squares), zanamivir (filled circles), and saline (open circles) (b) at 4 h before infection and 4 h and 17 h p.i. The number of surviving mice was monitored for 20 days p.i. (n = 10 to 12).

FIG. 4.

In vivo efficacy of the prophylactic intranasal administration of CS-8958 or zanamivir in a mouse influenza virus infection model. An intranasal dose of 0.5 μmol/kg of CS-8958 (filled squares), zanamivir (filled circles), or saline (open circles) was intranasally administered once at 10, 7, 4, or 1 day before infection (−10d, −7d, −4d, and −1d), and mice were infected with influenza A (A/PR/8/34) virus at 500 PFU/mouse on day 0. The dose of 0.5 μmol/kg corresponded to 236 μg/kg for CS-8958 and 166 μg/kg for zanamivir. The number of surviving mice was monitored for 20 days p.i. (n = 10). (Results were significant for the group given zanamivir at −1 day versus the group given saline [P = 0.0151]. Results were not significant for the three other zanamivir administration groups versus the saline administration group. Results were significant for all CS-8958 groups [P values of 0.0230 for the group dosed at −10 days and <0.0001 for the other three groups; log rank test]).