ABSTRACT BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4 + lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log 10 copies/ml, respectively, compared with 0.02 log 10 copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC 50 ) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration ( C trough ), adjusted by the baseline EC 50 ( C trough /EC 50 ), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted
