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Antimicrobial Agents and Chemotherapy, April 2001, p. 1162-1167, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1162-1167.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Comparison of the Anti-Influenza Virus Activity of RWJ-270201 with Those of Oseltamivir and Zanamivir

S. Bantia,1,* C. D. Parker,1 S. L. Ananth,1 L. L. Horn,1 K. Andries,2 P. Chand,1 P. L. Kotian,1 A. Dehghani,1 Y. El-Kattan,1 T. Lin,1 T. L. Hutchison,1 J. A. Montgomery,1 D. L. Kellog,1 and Y. S. Babu1

BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 35244,1 and Janssen Research Foundation, Beerse, Belgium2

Received 3 August 2000/Returned for modification 26 October 2000/Accepted 24 January 2001

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.

* Corresponding author. Mailing address: BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Dr., Birmingham, AL 35244. Phone: (205) 444-4619. Fax: (205) 444-4640. E-mail: sbantia{at}biocryst.com.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1162-1167, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1162-1167.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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