PRECLINICAL EVALUATION OF HBY-097, A NEW NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION

HEY 097 ylthiomethyl)-3,4-dihydroquinoxaline-2(1H)-thione] was selecte d from a series of quinoxalines as a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (NNRTI). H BY 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 wel l 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'-deox y-3'-azidothymidine, Mutant reverse transcriptases which arise as a co nsequence of treatment with other nonnucleoside inhibitors of HIV-1 re verse transcriptase were still inhibited by HEY 097 at relatively low concentrations. An HIV-1(MN) variant resistant to inhibition by HBY 09 7 displayed in the reverse transcriptase gene a mutation causing a sub stitution at position 190 of a glutamic acid for a glycine residue (G1 90-->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 i ts outstanding properties, HBY 097 was selected for further developmen t and is at present undergoing clinical trials.