A series of inhibitors of human immunodeficiency virus type 1 (HIV-1)
proteinase containing the 2-aralkyl-amino-substituted
statine moiety as a novel transition-state analog was synthesized, with the aim to obtain 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 amide, is a potent and orally bioavailable inhibitor of HIV-1 replication. The
antiviral activity of
SDZ PRI 053 was demonstrated in various cell lines, in primary lymphocytes, and in primary monocytes, against laboratory strains as well as clinical HIV-1 isolates (50% effective dose = 0.028 to 0.15 microM). Cell proliferation was impaired only at 100- to 300-fold-higher concentrations. The mechanism of
antiviral action of the
proteinase inhibitor SDZ PRI 0.53 was demonstrated to be inhibition of gag precursor
protein processing. The finding that the inhibitory 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 presence of
SDZ PRI 053 are about 50-fold less infectious than those from untreated 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 administration remained far above the concentrations needed to efficiently block HIV replication in vitro for a prolonged period. This compound is thus a promising candidate for clinical use in HIV disease.