Several series of indole and azaindole derivatives,derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (BMS-216),were characterized as inhibitors of HIV-1.These compounds inhibit virus attachment to cells by interfering with the interaction between the HIV-1 surface protein gp 120 and the host cell receptor CD4,the first step of the HIV-1 life cycle.Optimization of BMS-216 resulted in the identification of several clinical compounds,including the azaindoles BMS-377806 and BMS-488043.BMS-488043 was advanced into phase IIa clinical studies that established the potential of this class of compound to reduce viremia in HIV-1-infected individuals,whilst BMS-378806 protected macaque monkeys against a vaginally administered challenge with simian-human immunodeficiency virus (SHIV) when administered topically.The unique mechanism of HIV-1 attachment inhibitors results in no significant cross resistance to existing classes of anti-HIV drugs and offers additional potential benefits by disrupting interactions between viral gp 120 and host cells that do not lead to productive infection.