ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS ACTIVITY, BIOAVAILABILITY AND DRUG-RESISTANCE PROFILE OF THE NOVEL PROTEINASE-INHIBITOR MDL-74,695

MDL 74,695, a novel dipeptide-like compound containing the 'difluorost atone type' transition state mimic and a potent inhibitor of the human immunodeficiency virus (HIV) proteinase, was investigated for anti-HI V activity in vitro. The compound showed selective inhibition of both HIV-1 and HIV-2 in MT-4 cells. A potent antiviral effect against a ran ge of clinical isolates of HIV-1 cultured in human peripheral blood mo nonuclear cells and primary monocytes was also demonstrated. The antiv iral activity of MDL 74,695 against viruses resistant to a range of re verse transcriptase inhibitors was equivalent to the wild-type. In rat s MDL 74,695 (30 mg kg(-1)) was 4.9% orally bioavailable and maintaine d levels above the in vitro 50% inhibitory concentration (IC50) for ap proximately 3 h. Viruses with reduced sensitivity to MDL 74,695 and sa quinavir were selected in cell culture by continuous passage in increa sing drug concentrations, and first appeared after 20 and 17 passages, respectively. Amino acid changes were identified at positions 48 (gly cine to valine), 50 (isoleucine to valine) and 82 (valine to either is oleucine or alanine) in various combinations for MDL 74,695-resistant viruses. For saquinavir-resistant viruses changes were identified at p ositions 48 (glycine to valine) and 90 (leucine to methionine). Studie s using MDL 74,695, saquinavir and a third proteinase inhibitor indina vir, indicated that virus selected in the presence of MDI 74,695, with amino acid exchanges at positions 48 and 82 showed cross-resistance t o saquinavir. However, viruses selected in the presence of MDL 74,695 with amino acid exchanges at positions 50 and 82 showed no significant change in sensitivity to saquinavir. Likewise, viruses selected in th e presence of saquinavir with amino acid exchanges at positions 48 and 90 remained sensitive to MDL 74,695. All viruses selected after growt h in the presence of either MDL 74,695 or saquinavir showed little or no resistance to indinavir.