UC-38 was the lead compound for a group of structurally related non- nucleoside reverse transcriptase inhibitors with anti-HIV activity in the NCI primary in vitro anti-HIV drug screen. In past years, this project has employed pharmacokinetic and metabolic considerations to design structural congeners of UC-38 which showed low metabolism and improved oral bioavailability while retaining high activity against native strains of HIV. Since then, several congeners of UC-38 were shown to possess good activity against one or more HIV strains producing mutant reverse transcriptase. The priject objective was to evaluate the pharmacokinetic and metabolic properties of this group of UC-38 congeners in order to select a single compound with the greatest potential for development as an orally-administered anti-HIV drug. Twenty five UC-38 congeners were screened using a mouse liver homogenate assay. Murine pharmacokinetic studies were performed with thirteen congeners showing slow rates of in vitro metabolism, in order to evaluate structural elements influencing the rate of plasma clearance and the oral bioavailability. The primary determinant of plasma clearance following IV injection appeared to be the substitution to the isopropyl ester moiety of UC-38. In general, heptyl esters and oximes were cleared at a relatively slow rate as compared to ethers and unsaturated oximes. Oral bioavailability was influenced by substitutions to both the thiocarbamate and isopropyl ester entities of UC-38. When combined with an oxime, furylthioamides, followed by a phenylthioamide then thienylthioamides, demonstrated the highest bioavailabilities after oral administration. Heptyl esters were absorbed very poorly, regardless of the substitution to the thiocarbamate moiety. NSC 645129, a congener containing furylthioamide and t-butoxime moieties, showed significantly higher plasma levels and greater bioavailability (68%) than any of the other compounds tested after oral administration in mice. Following a single oral dose of NSC 645129 in dogs, plasma concentrations reached a maximum of 10 to 20 microM in 2 to 6 hours, and then decreased slowly to from 4 to 8 microM by 24 hours and to 2 microM by 48 hours. These plasma concentrations are far in excess of those required for in vitro efficacy against native or most mutant strains of HIV.
