Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication

Antimicrob Agents Chemother. 1995 Oct;39(10):2253-7. doi: 10.1128/aac.39.10.2253.

Abstract

HBY 097 [(S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroquinoxaline-2(1H)-thione] was selected from a series of quinoxalines as a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (NNRTI). HBY 097 was shown to be a highly potent inhibitor of HIV-1 induced cell killing and HIV-1 replication in a variety of human cell lines as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was also active against a variety of clinical isolates of HIV-1 including different HIV-1 subtypes and viruses resistant to 3'-deoxy-3'-azidothymidine. Mutant reverse transcriptases which arise as a consequence of treatment with other nonnucleoside inhibitors of HIV-1 reverse transcriptase were still inhibited by HBY 097 at relatively low concentrations. An HIV-1MN variant resistant to inhibition by HBY 097 displayed in the reverse transcriptase gene a mutation causing a substitution at position 190 of a glutamic acid for a glycine residue (G190 --> E), which is characteristic for quinoxaline derivatives. The drug was demonstrated to possess a favorable toxicity profile and to show good oral bioavailability in both mice and dogs. As a consequence of its outstanding properties, HBY 097 was selected for further development and is at present undergoing clinical trials.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Dogs
  • Drug Resistance
  • Female
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / physiology
  • Humans
  • Mice
  • Molecular Sequence Data
  • Quinoxalines
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Quinoxalines
  • Reverse Transcriptase Inhibitors
  • HBY 097