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 ‘difluorostatone type’ transition state mimic and a potent inhibitor of the human immunodeficiency virus (HIV) proteinase, was investigated for anti-HIV 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 range of clinical isolates of HIV-1 cultured in human peripheral blood mononuclear cells and primary monocytes was also demonstrated. The antiviral activity of MDL 74,695 against viruses resistant to a range of reverse transcriptase inhibitors was equivalent to the wild-type. In rats MDL 74,695 (30 mg kg−1) was 4.9% orally bioavailable and maintained levels above the in vitro 50% inhibitory concentration (IC50) for approximately 3 h. Viruses with reduced sensitivity to MDL 74,695 and saquinavir were selected in cell culture by continuous passage in increasing drug concentrations, and first appeared after 20 and 17 passages, respectively. Amino acid changes were identified at positions 48 (glycine to valine), 50 (isoleucine to valine) and 82 (valine to either isoleucine or alanine) in various combinations for MDL 74,695-resistant viruses. For saquinavir-resistant viruses changes were identified at positions 48 (glycine to valine) and 90 (leucine to methionine). Studies using MDL 74,695, saquinavir and a third proteinase inhibitor indinavir, indicated that virus selected in the presence of MDL 74,695, with amino acid exchanges at positions 48 and 82 showed cross-resistance to 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 the presence of saquinavir with amino acid exchanges at positions 48 and 90 remained sensitive to MDL 74,695. All viruses selected after growth in the presence of either MDL 74,695 or saquinavir showed little or no resistance to indinavir.