SCH 43478 and analogs: in vitro activity and in vivo efficacy of novel agents for herpesvirus type 2

Abstract

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 IC 50 for these compounds in plaque reduction analysis using Vero cells ranges from 0.8 to 2.0 μg/ml. All compounds have a LC 50>100 μg/ml in cytotoxicity analysis. Mechanism of action studies suggest that these molecules have an effect on the transactivation of viral immediate early ( α) 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 ( α) 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.