Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication.
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.
Kleim
J P
JP
Hoechst AG, Frankfurt, Germany.
Bender
R
R
Kirsch
R
R
Meichsner
C
C
Paessens
A
A
Rösner
M
M
Rübsamen-Waigmann
H
H
Kaiser
R
R
Wichers
M
M
Schneweis
K E
KE
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001483:Base Sequence; D004285:Dogs; D004351:Drug Resistance; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; C093110:HBY 097