ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans (acquired immunodeficiency syndrome/antiviral/peptidomimetic)

Examination of the structural basis for an- tiviral activity, oral pharmacokinetics, and hepatic metabo- lism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syn- drome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 (50% effective concentration (EC50) = 0.022-0.13 ,uM) and HIV-2 (EC50 = 0.16 ,uM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 ,ug/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease. H~~~~~~ N N~ I,>0 F -I OPh;H 0 OH N S ~~~~PhN ABT-538