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. 1994 Apr;38(4):688–692. doi: 10.1128/aac.38.4.688

Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro.

M Baba 1, S Shigeta 1, S Yuasa 1, H Takashima 1, K Sekiya 1, M Ubasawa 1, H Tanaka 1, T Miyasaka 1, R T Walker 1, E De Clercq 1
PMCID: PMC284526  PMID: 7518216

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.

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Selected References

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