Barrish J C, Gordon E, Alam M, Lin P F, Bisacchi G S, Chen P, Cheng P T, Fritz A W, Greytok J A, Hermsmeier M A
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
J Med Chem. 1994 Jun 10;37(12):1758-68. doi: 10.1021/jm00038a005.
A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h).
