AMINODIOL HIV PROTEASE INHIBITORS .1. DESIGN, SYNTHESIS, AND PRELIMINARY SAR

A series of HIV protease inhibitors containing a novel C-2 symmetrical ''aminodiol'' core structure were prepared from amino acid starting m aterials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated en zyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this ser ies led to aminodiol 9a (K-i = 100 nM; ED(50) (HIV-1) = 80 nM) contain ing P-1/P-1', benzyl and P-2/P-2' Boc substituents. Compound 9a is a s elective inhibitor of HIV protease versus other aspartyl proteases suc h as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstra tes similar activity in infected T-lymphocytes and PBMCs. After iv and oral administration in rats, 9a displayed significant oral bioavailab ility (ca. 40%) and a promising plasma elimination half-life (4 h).