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

We have recently reported an influenza virus neuraminidase inhibitor, RWJ-2 70201 (BCX-1812), a novel cyclopentane derivative discovered through struct ure-based drug design. In this paper, we compare the potency of three compo unds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all t ested influenza A and influenza 11 neuraminidases in vitro, with 50% inhibi tory 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 (GG1 67), RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influ enza virus neuraminidase over mammalian, bacterial, or other viral neuramin idases. Oral administration of a dosage of 1 mg/kg of body weight/day of RW J-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the mur ine model of influenza virus infection as determined by lethality and weigh t loss protection, RWJ-270201 administered intranasally at 0.01 mg/kg/day i n the murine influenza model demonstrated complete protection against letha lity, whereas oseltamivir carboxylate and zanamivir at the same dose demons trated only partial protection, In the delayed-treatment murine influenza m odel, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamiv ir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant p rotection against lethality (P < 0.001 versus control). However, when the t reatment was delayed for 48 h, no significant protection was observed in ei ther drug group. No drug-related toxicity was observed in mice receiving 10 0 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles ju stify further consideration of RWJ-270201 for the treatment and prevention of human influenza.