title: 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.
abstract: Bisheteroarylpiperazine compounds are nonnucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1 (HIV-1). To provide a rationale for combination therapy with a second-generation bisheteroarylpiperazine, we investigated the effect of U-90152 in combination with 3'-azido-3'-deoxythymidine (AZT) or 2',3'-dideoxycytidine (ddC). HIV-1-infected cells were cultured in the presence of test compounds, and drug effects on p24 core antigen production were measured by an enzyme-linked immunosorbent assay. In a CD4+ T-cell line (H9) infected with HIV-1IIIB, the 50% effective concentrations for U-90152, AZT, and ddC were 6.0, 80.4, and 31.8 nM, respectively. In human peripheral blood mononuclear cells infected with the molecularly cloned clinical isolate HIV-1JRCSF, the 50% effective concentrations for U-90152, AZT, and ddC were 5.3, 5.9, and 25.0 nM, respectively. Over a range of drug concentrations (U-90152 and AZT at 0.3, 1, 3, 10, and 30 nM; ddC at 3, 10, 30, and 100 nM), U-90152 in combination with AZT or ddC synergistically inhibited the replication of a laboratory-adapted strain and a clinical isolate of HIV-1.
authors.affiliation: Upjohn Laboratories, Kalamazoo, Michigan 49001.
authors.forename: K T
authors.initials: KT
authors.lastname: Chong
authors.forename: P J
authors.initials: PJ
authors.lastname: Pagano
authors.forename: R R
authors.initials: RR
authors.lastname: Hinshaw
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000382:microbiology; D000998:Antiviral Agents / Q000494:pharmacology*; D020008:Delavirdine; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D010879:Piperazines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects*; D016047:Zalcitabine / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D007211:Indoles; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016047:Zalcitabine; D020008:Delavirdine; D054303:HIV Reverse Transcriptase