| CS-8958 as the prodrug of R-125489 which is a new neuraminidase (NA) inhibitor reveals long-acting anti-influenza virus activity. CS-8958 displays comparably weak inhibitory activities against the 1934 isolate (A/PR/8/34) and the 1968 isolate (A/Aichi/2/68) with mean IC50 of 822 and 114 nM, respectively. CS-8958 basically shows no inhibitory activities against some strains of B viruses, with an IC50 of mean 10 μM. The IC50 of CS-8958 for H2N2 (A/Singapore/1/57) virus is 128 nM. However, R-125489 reveals potent NA inhibitory role with IC50s of 2.49 nM for some strains of H1N1 viruses. The mean IC50 of R-125489 against H3N2 viruses is 16.7 nM. CS-8958 has either no or weak inhibitory activities with a minimal IC50 of 142 nM against animal influenza virus subtypes N3 to N9 and H5N1 virus while the minimal IC50 of R-125489 is 1.81 nM. Mice that treated with CS-8958, have the highest survival rate, and more than half the mice given CS-8958 survived for 20 days p.i. Importantly, all mice infected with 500 PFU of A/PR/8/34 survive after three injections of CS-8958 at a dose of 0.2 μmol/kg.[1] CS-8958 at a single dose of 1,500 μg/kg which is given to mice 2 hours post-infection with H5N1 influenza viruses generates a higher survival rate than did continuous five-day injections of oseltamivir at a dose of 50 mg/kg twice daily. CS-8958 is also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. For seven days prior to virus infection, a single injection of CS-8958 also protects mice against H5N1 virus lethal infection.[2] In pharmacokinetics, after intratracheal injection of CS-8958, plasma R-125489 concentration is slowly eliminated, and its half-life (14.1 hours) is considerably longer than that after intravenous injection of R-125489. The radioactivity of intratracheally injected 14C-CS-8958 is mainly excreted into the urine (accounting for 67.5% of dose). R-125489 possessed most of the urinary radioactivity recovered after 24 hours. [3] |
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