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Antimicrobial Agents and Chemotherapy, March 2001, p. 743-748, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.743-748.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cyclopentane Neuraminidase Inhibitors with Potent In Vitro Anti-Influenza Virus Activities

Donald F. Smee,* John H. Huffman, Ann C. Morrison, Dale L. Barnard, and Robert W. Sidwell

Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600

Received 12 July 2000/Returned for modification 11 October 2000/Accepted 30 November 2000

A novel series of cyclopentane derivatives have been found to exhibit potent and selective inhibitory effects on influenza virus neuraminidase. These compounds, designated RWJ-270201, BCX-1827, BCX-1898, and BCX-1923, were tested in parallel with zanamivir and oseltamivir carboxylate against a spectrum of influenza A (H1N1, H3N2, and H5N1) and influenza B viruses in MDCK cells. Inhibition of viral cytopathic effect ascertained visually and by neutral red dye uptake was used, with 50% effective (virus-inhibitory) concentrations (EC50) determined. Against the H1N1 viruses A/Bayern/07/95, A/Beijing/262/95, A/PR/8/34, and A/Texas/36/91, EC50s (determined by neutral red assay) of the novel compounds were <= 1.5 µM. Twelve strains of H3N2 and two strains of avian H5N1 viruses were inhibited at <0.3 µM. Influenza B/Beijing/184/93 and B/Harbin/07/94 viruses were inhibited at <0.2 µM, with three other B virus strains inhibited at 0.8 to 8 µM. The novel inhibitors were comparable in potency to (or slightly more potent than) zanamivir and oseltamivir carboxylate. No cytotoxicity was seen with the compounds at concentrations of <= 1 mM in cell proliferation assays. The antiviral activity of RWJ-270201, chosen for clinical development, was studied in greater detail. Its potency and that of oseltamivir carboxylate decreased with increasing multiplicity of virus infection. Time-of-addition studies indicated that treatment with either compound needed to begin 0 to 12 h after virus exposure for optimal activity. Exposure of cells to RWJ-270201 caused most of the virus to remain cell associated, with extracellular virus decreasing in a concentration-dependent manner. This is consistent with its effect as a neuraminidase inhibitor. RWJ-270201 shows promise in the treatment of human influenza virus infections.

* Corresponding author. Mailing address: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600. Phone: (435) 797-2897. Fax: (435) 797-3959. E-mail: dsmee{at}cc.usu.edu.

Antimicrobial Agents and Chemotherapy, March 2001, p. 743-748, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.743-748.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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