Document 0102
 DOCN  M9650102
 TI    Potent human immunodeficiency virus type 1 protease inhibitors that
       utilize noncoded D-amino acids as P2/P3 ligands.
 DT    9605
 AU    Jungheim LN; Shepherd TA; Baxter AJ; Burgess J; Hatch SD; Lubbehusen P;
       Wiskerchen M; Muesing MA; Lilly Research Laboratories, Eli Lilly and
       Company, Indianapolis,; Indiana 46285-1523, USA.
 SO    J Med Chem. 1996 Jan 5;39(1):96-108. Unique Identifier : AIDSLINE
       MED/96136792
 AB    Noncoded D-amino acids have been designed to replace the quinaldic
       amide-asparaginyl moiety (P2/P3 ligand) found in several potent human
       immunodeficiency virus (HIV) protease inhibitors such as LY289612. The
       substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a
       CH2CONH2 (asparagine side chain mimic), while the amino acid side chain
       became the backbone and P3 ligand of these novel inhibitors. Compounds
       derived from S-aryl-D-cysteine proved to be potent HIV protease
       inhibitors which also exhibited potent whole cell antiviral activity.
       Oxidation of the cysteines to the sulfoxide or sulfone oxidation states
       resulted in significant improvements in potency. For example, the
       compound derived from N-(methyl-sulfonyl)-2-S-naphthylcysteine sulfone,
       17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread
       of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were
       found to be orally bioavailable in a rat model.
 DE    Amino Acids/METABOLISM  Animal  Antiviral Agents/CHEMISTRY/*CHEMICAL
       SYNTHESIS/METABOLISM/  PHARMACOLOGY  Biological Availability
       Cysteine/*ANALOGS & DERIVATIVES  Drug Design  Human  HIV
       Protease/*METABOLISM  HIV Protease Inhibitors/*CHEMICAL
       SYNTHESIS/METABOLISM/  PHARMACOLOGY  HIV-1/*DRUG EFFECTS/ENZYMOLOGY
       Ligands  Male  Molecular Structure  Nuclear Magnetic Resonance  Protein
       Binding  Rats  Rats, Sprague-Dawley  Spectrum Analysis, Mass
       Structure-Activity Relationship  Sulfones/CHEMICAL
       SYNTHESIS/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).