Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities.

Abstract

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 (EC(50)) determined. Against the H1N1 viruses A/Bayern/07/95, A/Beijing/262/95, A/PR/8/34, and A/Texas/36/91, EC(50)s (determined by neutral red assay) of the novel compounds were < or =1.5 microM. Twelve strains of H3N2 and two strains of avian H5N1 viruses were inhibited at <0.3 microM. Influenza B/Beijing/184/93 and B/Harbin/07/94 viruses were inhibited at <0.2 microM, with three other B virus strains inhibited at 0.8 to 8 microM. 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 < or =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.

• Authors: D F Smee, J H Huffman, A C Morrison, D L Barnard, R W Sidwell
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 45 Issue 3 Pg. 743-8 (Mar 2001) ISSN: 0066-4804 [Print] United States
• PMID: 11181354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acids, Carbocyclic
• Antiviral Agents
• Cyclopentanes
• Guanidines
• Ribavirin
• Neuraminidase
• peramivir

Topics

• Acids, Carbocyclic
• Antiviral Agents (pharmacology)
• Cyclopentanes (pharmacology)
• Guanidines
• Influenza A virus (drug effects, physiology)
• Influenza B virus (drug effects, physiology)
• Microbial Sensitivity Tests
• Neuraminidase (antagonists & inhibitors, metabolism)
• Ribavirin (pharmacology)
• Time Factors
• Virus Replication (drug effects)