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

Antimicrob Agents Chemother. 1994 Apr;38(4):688-92. doi: 10.1128/AAC.38.4.688.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Drug Resistance, Microbial
  • Drug Synergism
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-2 / drug effects
  • Humans
  • Reverse Transcriptase Inhibitors
  • Uracil / analogs & derivatives*
  • Uracil / pharmacology
  • Virus Replication / drug effects
  • Zidovudine / pharmacology

Substances

  • Antiviral Agents
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • Uracil
  • HIV Reverse Transcriptase
  • emivirine