CL387626 exhibits marked and unusual antiviral activity against respiratory syncytial virus in tissue culture and in cotton rats

Abstract

CL387626 (4,4′-Bis[4,6-di[3-aminophenyl- N, N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino-biphenyl-2,2′-disulfonic acid, disodium salt), a compound synthesized by Wyeth-Ayerst Research Laboratories, was tested for its cytotoxicity and antiviral activity against respiratory syncytial virus (RSV) in tissue culture and in cotton rats. The median cell inhibitory (IC 50) and median efficacious (EC 50) concentrations of CL387626 against RSV in proliferating HEp2 or Vero tissue culture cells were determined to be 375 and 0.25 μg/ml, respectively, giving the compound an apparent selective index (S.I.) of 1500. This compound also exhibited uncommon antiviral activity against RSV in cotton rats. In multiple experiments, a single 30 mg/kg dose of CL387626 administered intranasally 4 or 5 days prior to virus challenge, significantly inhibited pulmonary replication of RSV compared to that seen in control animals inoculated similarly with placebo (i.e. water). In contrast to these results, most lots of CL387626 failed to significantly inhibit pulmonary RSV replication when administered utilizing therapeutic administration schedules. Although some cytotoxicity was noted in tissue culture assays, no overt toxic effects were noted in any test animal, including those inoculated with >300 mg CL387626/kg, a dose approximately 150 times the apparent minimal efficacious dose (i.e. 1.9 mg/kg).