BISHETEROARYLPIPERAZINE REVERSE-TRANSCRIPTASE INHIBITOR IN COMBINATION WITH 3'-AZIDO-3'-DEOXYTHYMIDINE OR 2',3'-DIDEOXYCYTIDINE SYNERGISTICALLY INHIBITS HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION IN-VITRO

Bisheteroarylpiperazine compounds are nonnucleoside reverse transcript ase inhibitors of human immunodeficiency virus type 1 (HIV-1). To prov ide a rationale for combination therapy with a second-generation bishe teroarylpiperazine, we investigated the effect of U-90152 in combinati on with 3'-azido 3'-deoxythymidine (AZT) or 2',3'-dideoxycytidine (ddC ). HTV-1-infected cells were cultured in the presence of test compound s, and drug effects on p24 core antigen production were measured by an enzyme-linked immunosorbent assay. In a CD4(+) T cell line (H9) infec ted with HIV-1(IIIB) the 50% effective concentrations for U-90152, AZT , and ddC were 6.0, 80.4, and 31.8 nM, respectively. In human peripher al blood mononuclear cells infected with the molecularly cloned clinic al isolate HIV-1(JRCSF), the 50% effective concentrations for U-90152, AZT, and ddC were 5.3, 5.9, and 25.0 nM, respectively. Over a range o f drug concentrations (U-90152 and AZT at 0.3, 1, 3, 10, and 30 nM; dd C at 3, 10, 30, and 100 nM), U-90152 in combination with AZT or ddC sy nergistically inhibited the replication of a laboratory-adapted strain and a clinical isolate of HIV-1.