SCH 43478 and analogs: in vitro activity and in vivo efficacy of novel agents for herpesvirus type 2.
SCH 43478 and analogs are a class of non-nucleoside antiviral agents that have potent and selective activity against herpes simplex virus type 2 (HSV-2). The IC50 for these compounds in plaque reduction analysis using Vero cells ranges from 0.8 to 2.0 microg/ml. All compounds have a LC50 > 100 microg/ml in cytotoxicity analysis. Mechanism of action studies suggest that these molecules have an effect on the transactivation of viral immediate early (alpha) gene expression. Time of addition studies indicate that antiviral activity of these analogs is limited to the initial 2-3 h after infection and is not due to inhibition of viral adsorption or penetration. Analysis of HSV protein expression demonstrates that SCH 49286 inhibits the accumulation of viral immediate early (alpha) gene products. SCH 43478 demonstrates statistically significant efficacy (P < 0.05) in the guinea pig genital model of HSV infection. Following subcutaneous administration in a therapeutic treatment regimen, SCH 43478 (90 mg/kg/day) is efficacious in reducing the number and severity of lesions and the neurological complications of acute HSV infection. Thus, SCH 43478 and analogs are anti-herpesvirus agents with a unique mechanism of action.
Albin
R
R
Department of Antiviral Chemotherapy, Schering-Plough Research Institute, Kenilworth, NJ 07003, USA.
Chase
R
R
Risano
C
C
Lieberman
M
M
Ferrari
E
E
Skelton
A
A
Buontempo
P
P
Cox
S
S
DeMartino
J
J
Wright-Minogue
J
J
Jirau-Lucca
G
G
Kelly
J
J
Afonso
A
A
Kwong
A D
AD
Rozhon
E J
EJ
O'Connell
J F
JF
D000327:Adsorption; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D005347:Fibroblasts; D006168:Guinea Pigs; D006367:HeLa Cells; D006558:Herpes Genitalis / Q000188:drug therapy / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007279:Injections, Subcutaneous; D007700:Kinetics; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
D000998:Antiviral Agents; D017874:Immediate-Early Proteins; D011720:Pyrazoles; D011804:Quinolines; C108468:SCH 43478; C108469:SCH 46792; C108470:SCH 49286