Document 0086
 DOCN  M9480086
 TI    Aminodiol HIV protease inhibitors. 1. Design, synthesis, and preliminary
       SAR.
 DT    9410
 AU    Barrish JC; Gordon E; Alam M; Lin PF; Bisacchi GS; Chen P; Cheng PT;
       Fritz AW; Greytok JA; Hermsmeier MA; Bristol-Myers Squibb Pharmaceutical
       Research Institute,; Princeton, New Jersey 08543-4000.
 SO    J Med Chem. 1994 Jun 10;37(12):1758-68. Unique Identifier : AIDSLINE
       MED/94293294
 AB    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).
 DE    Amino Alcohols/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Animal  Antiviral
       Agents/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Cells, Cultured  *Drug Design
       Human  HIV/*DRUG EFFECTS/ENZYMOLOGY  HIV Protease/*METABOLISM  HIV
       Protease Inhibitors/*CHEMICAL SYNTHESIS/PHARMACOLOGY  HIV-1/DRUG EFFECTS
       HIV-2/DRUG EFFECTS  Male  Rats  Rats, Sprague-Dawley  Structure-Activity
       Relationship  Swine  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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