SCH 48973: a potent, broad-spectrum, antienterovirus compound.
SCH 48973 is a novel molecule with potent, selective, antienterovirus activity. In assays of the cytopathic effect against five picornaviruses, SCH 48973 had antiviral activity (50% inhibitory concentrations [IC50s]) of 0.02 to 0.11 microg/ml, with no detectable cytotoxicity at 50 microg/ml. SCH 48973 inhibited 80% of 154 recent human enterovirus isolates at an IC50 of 0.9 microg/ml. The antiviral activity of SCH 48973 is derived from its specific interaction with viral capsid, as confirmed by competition binding studies. The affinity constant (Ki) for SCH 48973 binding to poliovirus was 8.85 x 10(-8) M. In kinetic studies, a maximum of approximately 44 molecules of SCH 48973 were bound to poliovirus capsid. SCH 48973 demonstrated efficacy in a murine poliovirus model of enterovirus disease. SCH 48973 increased the survival of infected mice when it was administered orally at dosages of 3 to 20 mg/kg of body weight/day. Oral administration of SCH 48973 also reduced viral titers in the brains of infected mice. On the basis of its in vitro and in vivo profiles, SCH 48973 represents a potential candidate for therapeutic intervention against enterovirus infections.
Buontempo
P J
PJ
Department of Antiviral Chemotherapy, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Cox
S
S
Wright-Minogue
J
J
DeMartino
J L
JL
Skelton
A M
AM
Ferrari
E
E
Albin
R
R
Rozhon
E J
EJ
Girijavallabhan
V
V
Modlin
J F
JF
O'Connell
J F
JF
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000821:virology; D004770:Enterovirus / Q000187:drug effects* / Q000378:metabolism; D004769:Enterovirus Infections; D055768:Halogenated Diphenyl Ethers; D007700:Kinetics; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010647:Phenyl Ethers / Q000493:pharmacokinetics / Q000494:pharmacology*; D011051:Poliomyelitis / Q000188:drug therapy / Q000821:virology; D012680:Sensitivity and Specificity
D000998:Antiviral Agents; D055768:Halogenated Diphenyl Ethers; D010647:Phenyl Ethers; C000619933:pocapavir