Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir

Abstract

We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design. In this paper, we compare the potency of three compounds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all tested influenza A and influenza B neuraminidases in vitro, with 50% inhibitory concentrations of 0.09 to 1.4 nM for influenza A neuraminidases and 0.6 to 11 nM for influenza B neuraminidases. These values were comparable to or lower than those for oseltamivir carboxylate (GS4071) and zanamivir (GG167). RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influenza virus neuraminidase over mammalian, bacterial, or other viral neuraminidases. Oral administration of a dosage of 1 mg/kg of body weight/day of RWJ-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the murine model of influenza virus infection as determined by lethality and weight loss protection. RWJ-270201 administered intranasally at 0.01 mg/kg/day in the murine influenza model demonstrated complete protection against lethality, whereas oseltamivir carboxylate and zanamivir at the same dose demonstrated only partial protection. In the delayed-treatment murine influenza model, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamivir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant protection against lethality (P < 0.001 versus control). However, when the treatment was delayed for 48 h, no significant protection was observed in either drug group. No drug-related toxicity was observed in mice receiving 100 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles justify further consideration of RWJ-270201 for the treatment and prevention of human influenza.

FIG. 1

Structures of compounds under investigation.

FIG. 2

Effects of oral treatment of RWJ-270201 and oseltamivir, at 10 mg/kg/day given 24 h postinfection, on weight loss in influenza A (H6N2)-infected mice. The number of mice in each group was 10 except for the vehicle infected group (n = 8) and vehicle uninfected group (n = 5). ●, vehicle uninfected group; ○, vehicle infected group; ■, RWJ-270201 treatment group; ▾, oseltamivir treatment group.

FIG. 3

Effects of intranasal treatment of RWJ-270201, oseltamivir carboxylate, and zanamivir, at a dose of 0.1 mg/kg/day, on weight loss in influenza A (H6N2)-infected mice. The number of mice in each group was 10 except for the vehicle uninfected group (n = 5). ●, vehicle uninfected group; ○, vehicle infected group; ■, RWJ-270201 treatment group; ▾, oseltamivir carboxylate treatment group; ⧫, zanamivir treatment group.