title: Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro.
abstract: MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil or I-EBU) has recently been identified as a highly potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. Since the compound has favorable pharmacokinetic and toxicity profiles in vivo, we have evaluated MKC-442 for its inhibitory effect on the replication of HIV-1 in various cell cultures, including human peripheral blood lymphocytes and monocyte-macrophages. The 50 and 90% effective concentrations for HIV-1 (HTLV-IIIB strain) replication in MT-4 cells were 15 and 98 nM, respectively. MKC-442 was also inhibitory to HIV-1 replication in peripheral blood lymphocytes and monocyte-macrophages as determined by the production of p24 antigens in the culture supernatant. Fluorescence-activated cell sorter analysis revealed that MKC-442 was equally active against zidovudine-resistant mutants and zidovudine-susceptible strains. Furthermore, combinations of MKC-442 with either 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, or 2',3'-dideoxyinosine synergistically inhibited the replication of HIV-1. Thus, MKC-442 has been considered as a candidate for clinical efficacy studies.
authors.affiliation: Department of Microbiology, Fukushima Medical College, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: S
authors.initials: S
authors.lastname: Yuasa
authors.forename: H
authors.initials: H
authors.lastname: Takashima
authors.forename: K
authors.initials: K
authors.lastname: Sekiya
authors.forename: M
authors.initials: M
authors.lastname: Ubasawa
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Miyasaka
authors.forename: R T
authors.initials: RT
authors.lastname: Walker
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D014498:Uracil; D054303:HIV Reverse Transcriptase; C083858:emivirine