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 OC 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 OC 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. Pharmacokinetic properties of a t- butoxime and i-propoxime thiocarbamate, and a t-butoxime furylthioamide were studied in dogs following intravascular and intragastric administration. The t-butoxime thiocarbamate exhibited significantly lower total body clearance (higher plasma concentrations) as compared to either the i-propoxime thiocarbamate or the t-butoxime furylthioamide, suggesting lower metabolism or excretion. Both of the t-butoximes showed significantly greater oral bioavailability than did the i-propoxime. All of the compounds showed plasma concentrations 24 hours following a single intragastric dose of 300 mumol/kg in dogs which were in excess of those required for inhibition of HIV-induced in vitro cytopathology.
