SDZ-PRI-053, AN ORALLY BIOAVAILABLE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEINASE-INHIBITOR CONTAINING THE 2-AMINOBENZYLSTATINE MOIETY

A series of inhibitors of human immunodeficiency virus type 1 (HIV-1) proteinase containing the 2-aralkyl-amino-substituted statine moiety a s a novel transition-state analog was synthesized, with the aim to obt ain compounds which combine anti-HIV potency with oral bioavailability , The reduced-size 2-aminobenzylstatine derivative SDZ PRI 053, which contains 2-(S)-amino-3-(R)-hydroxyindane in place of an amino acid ami de, is a potent and orally bioavailable inhibitor of HIV-1 replication , The antiviral activity of SDZ PRI 053 was demonstrated in various ce ll lines, in primary lymphocytes, and in primary monocytes, against la boratory strains as well as clinical HIV-1 isolates (50% effective dos e = 0.028 to 0.15 mu M). Cell proliferation was impaired only at 100- to 300-fold-higher concentrations. The mechanism of antiviral action o f the proteinase inhibitor SDZ PRI 053 was demonstrated to be inhibiti on of gag precursor protein processing, The finding that the inhibitor y potency of SDZ PRI 053 in chronic virus infection, determined by p24 release, was considerably lower than that in de novo infection may be explained by the fact that the virus particles produced in the presen ce of SDZ PRI 053 are about 50-fold less infectious than those from un treated cultures, Upon intravenous administration, half-lives in blood of 100 and 32 min in mice and rats, respectively, were measured. Oral bioavailability of SDZ PRI 053 in rodents was 20 to 60%, depending on the dose. In mice, rats, and dogs, the inhibitor levels after oral ad ministration remained far above the concentrations needed to efficient ly block HIV replication in vitro for a prolonged period, This compoun d is thus a promising candidate for clinical use in HIV disease.