In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity.
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 (IC(50)s) for the two compounds ranged from 0.5 nM to 6,701 nM. The compounds also inhibited EV, including coxsackie A and B viruses (IC(50) = 773 to 3,608 nM) and echoviruses (IC(50) = 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 IC(50)s 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.
Barnard
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DL
Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600, USA. honery@cc.usu.edu
Hubbard
V D
VD
Smee
D F
DF
Sidwell
R W
RW
Watson
K G W
KG
Tucker
S P T
SP
Reece
P A R
PA
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001682:Biological Availability; D002213:Capsid / Q000187:drug effects*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004770:Enterovirus / Q000187:drug effects; D029822:Enterovirus B, Human / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D007624:KB Cells; D009499:Neutral Red; D010091:Oximes / Q000494:pharmacology*; D010849:Picornaviridae / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D010091:Oximes; D010880:Piperidines; D011724:Pyridazines; D009499:Neutral Red; C074589:pirodavir