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Antimicrobial Agents and Chemotherapy, May 2004, p. 1766-1772, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1766-1772.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Expanded-Spectrum Pyridazinyl Oxime Ethers Related to Pirodavir: Novel Capsid-Binding Inhibitors with Potent Antipicornavirus Activity

D. L. Barnard,^1* V. D. Hubbard,¹ D. F. Smee,¹ R. W. Sidwell,¹ K. G. W. Watson,^2, S. P. T. Tucker,² and P. A. R. Reece²

Institute for Antiviral Research, Utah State University, Logan, Utah,¹ Biota Holdings Ltd., Melbourne, Victoria, Australia²

Received 14 May 2003/ Returned for modification 18 September 2003/ Accepted 21 January 2004

Picornaviruses (PV) include human rhinovirus (HRV), the primary cause of the common cold, and the enteroviruses (EV), which cause serious diseases such as poliomyelitis, meningoencephalitis, and systemic neonatal disease. Although no compounds for PV infections have been approved in the United States, pirodavir was one of the most promising capsid-binding compounds to show efficacy in human clinical trials for chemoprophylaxis of the common cold. Susceptibility to hydrolysis precluded its use as an oral agent. We have developed orally bioavailable pyridazinyl oxime ethers that are as potent as pirodavir. Compounds BTA39 and BTA188 inhibited a total of 56 HRV laboratory strains and three clinical isolates as determined by neutral red uptake assay. At concentrations of <100 nM, BTA39 inhibited 69% of the HRV serotypes and isolates evaluated, BTA188 inhibited 75%, and pirodavir inhibited 59% of the serotypes and isolates. The 50% inhibitory concentrations (IC₅₀s) for the two compounds ranged from 0.5 nM to 6,701 nM. The compounds also inhibited EV, including coxsackie A and B viruses (IC₅₀ = 773 to 3,608 nM) and echoviruses (IC₅₀ = 193 to 5,155 nM). BTA39 only inhibited poliovirus strain WM-1 at 204 nM, and BTA188 only inhibited poliovirus strain Chat at 82 nM. EV 71 was inhibited by BTA39 and BTA188, with IC₅₀s of 1 and 82 nM, respectively. Both compounds were relatively nontoxic in actively growing cells (50% cytotoxic doses, 4,588 nM). These data suggest that these oxime ethers warrant further investigation as potential agents for treating selected PV infections.

Present address: Chemistry Synthesis Group, Structural Biology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Victoria 3050, Australia.