Oxathiin carboxanilide (OC, NSC 615985) and UC-38 NSC (629243) are potent inhibitors of in vitro HIV-induced cytopathology, but rapid metabolism and poor oral bioavailability in vivo will limit their potential clinical usefulness. The purpose of this project was to employ pharmacokinetic and metabolic considerations to design congeners of these molecules with lower rates of metabolism and improved oral bioavailability, while retaining high anti-HIV activity. Experimental evidence suggested that metabolic degradation of 0C and UC-38 was primarily due to cleavage by esterases of the isopropyl ester moiety and to a lesser extent the oxathiin or thiocarbamate moieties in these molecules. Therefore, the selection of available analogs for examination, and subsequent structural alterations proposed for newly synthesized compounds, focussed on these moieties. Existing analogs- were initially evaluated for in vitro metabolism using a hamster liver homogenate assay, and new compounds were designed and synthesized based on the initial results. Murine intravenous and oral pharmacokinetic studies were performed on 12 compounds showing no or minimal metabolic degradation in vitro. All of the compounds showed lower total body clearance when compared to 0C and UC-38. Modification of the isopropyl ester moiety, as predicted, had the greatest effect on total body clearance, with oximes and hindered esters showing the lowest clearance values. Alteration of the thiocarbamate moiety dramatically affected the oral bioavailability. Thiocarbamates showed significantly greater bioavailability than did either heterocyclic or aryl thioamides following intragastric administration.
