EFFICACY, PHARMACOKINETICS, AND IN-VIVO ANTIVIRAL ACTIVITY OF UC781, A HIGHLY POTENT, ORALLY BIOAVAILABLE NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR OF HIV TYPE-1

A series of compounds related to oxathiin carboxanilide has been ident ified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) of HI V-1, and structure-activity relationships have been described (Buckhei t RW, et al.: Antinicrob Agents Chemother 1995;39:2718-2727). Three ne w analogs (UC040, UC82, and UC781) inhibited laboratory and clinical i solates of HIV-1, including isolates representative of the various cla des of HIV-1 found worldwide, in both established and fresh human cell s, Virus isolates with the amino acid changes L100I, K103N, V106I, and Y181C in the reverse transcriptase were partially resistant to these compounds, However, UC781 inhibited these virus isolates at low nontox ic concentrations, presenting a broad in vitro therapeutic index, As w ith other NNRTIs, each of the compounds synergistically interacted wit h AZT to inhibit HIV-1 replication, UC781 possesses a favorable pharma cokinetic profile in mice with a high level of oral bioavailability, P lasma concentrations reached maximum levels within 2 to 4 br of oral a dministration and remained in excess of those required for in vitro an ti-HIV activity for at least 24 hr after a single oral dose, When eval uated in a murine hollow fiber implant model of HIV infection, UC781 d osed orally or parenterally was able to suppress HIV replication compl etely in this model system, providing evidence of the in vivo efficacy of the compound.