RD3-0028

RD3-0028, a benzodithiin compound, has antiviral activity against respiratory syncytial virus (RSV) in cell culture. We used a mouse model of RSV infection to determine the in vivo effect of RD3-0028. Cyclophosphamide (CYP)-treated, immunosuppressed mice were inoculated intranasally. The lungs of the mice were removed on day 4. The virus titers of the lungs of RD3-0028-treated mice were compared to the virus titers of the lungs of virus-inoculated, untreated control mice. In an effort to increase the therapeutic effectiveness of this compound, RD3-0028 was administered by aerosol to RSV-infected mice by using a head-exposure system. Aerosols generated from reservoirs containing RD3-0028 (7 mg/ml) administered for 2 h twice daily for 3 days significantly reduced the pulmonary titer of RSV-infected mice. It is clear that the minimal effective dose of RD3-0028 for RSV-infected mice is significantly less than that of ribavirin, the only compound currently available for use against RSV disease. Furthermore, the RD3-0028 aerosol administration appeared to protect the lungs of infected, CYP-treated mice against tissue damage, as evidenced by the preservation of the lung architecture and a reduction in pulmonary inflammatory infiltrates. RD3-0028 aerosol was not toxic for mice at the therapeutic dose. The present study demonstrates the effectiveness of aerosol administration of RD3-0028 for RSV-infected mice.

Benzodithiin derivatives are highly potent and specific inhibitors of respiratory syncytial virus (RSV) replication in vitro. The most potent and selective congener of a benzodithiin derivative is 1,4-dihydro-2,3-benzodithiin(RD3-0028). According to the modified 3-(4,5-dimethylthiazole-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) assay developed in our laboratories, this compound has a 50% effective concentration of 4.5 microM and a 50% cytotoxic concentration of 271.0 microM, which is superior to that of ribavirin. This compound also inhibits RSV strain subgroups A and B and clinical isolates. RD3-0028, however, does not inhibit the replication of influenza A virus, measles virus, herpes simplex virus types 1 and 2, or human cytomegalovirus. Two other benzodithiin derivatives [1,4-dihydro-6-methyl-2,3-benzodithiin (RD3-0270) and 1,4-dihydro-5-methyl-1-2,3-benzodithiin (RD3-0284)] also inhibit RSV replication at a selectivity index greater a factor of 20. These results suggest that the benzodithiin skeleton is an important structure for inhibitory activity against RSV replication.