The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC 50 s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC 50 of <21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC 50 of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml ␣-1 acid glycoprotein increased the IC 50 approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.New antiretroviral drugs are currently needed, and more will be required in the future, to treat drug-resistant strains emerging from current therapies (8). The nonnucleoside reverse transcriptase inhibitor (NNRTI) compound class is a key component of effective combination regimens. However, in the absence of complete suppression of human immunodeficiency virus type 1 (HIV-1) replication, resistance to NNRTIs emerges rapidly due to a low genetic barrier.We have recently described results obtained with analogs in a benzophenone compound series that were synthesized and screened for anti-HIV-1 activity, with particular emphasis on potency against key NNRTI-resistant HIV-1 strains emerging from current treatments (6).