Document 0417
 DOCN  M9650417
 TI    A novel, picomolar inhibitor of human immunodeficiency virus type 1
       protease.
 DT    9605
 AU    Sham HL; Zhao C; Stewart KD; Betebenner DA; Lin S; Park CH; Kong XP;
       Rosenbrook W Jr; Herrin T; Madigan D; Vasavanonda S; Lyons N; Molla A;
       Saldivar A; Marsh KC; McDonald E; Wideburg NE; Denissen JF; Robins T;
       Kempf DJ; Plattner JJ; Norbeck DW; Pharmaceutical Products Division,
       Abbott Laboratories, Abbott; Park, Illinois 60064-3500.
 SO    J Med Chem. 1996 Jan 19;39(2):392-7. Unique Identifier : AIDSLINE
       MED/96145172
 AB    The design, synthesis, and molecular modeling studies of a novel series
       of azacyclic ureas, which are inhibitors of human immunodeficiency virus
       type 1 (HIV-1) protease that incorporate different ligands for the S1',
       S2, and S2' substrate-binding sites of HIV-1 protease are described. The
       synthesis of this series is highly flexible in the sense that the P1',
       P2, and P2' residues of the inhibitors can be changed independently.
       Molecular modeling studies on the phenyl ring of the P2 and P2' ligand
       suggested incorporation of hydrogen-bonding donor/acceptor groups at the
       3' and 4-positions of the phenyl ring should increase binding potency.
       This led to the discovery of compound 7f (A-98881), which possesses high
       potency in the HIV-1 protease inhibition assay and the in vitro MT-4
       cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM).
       This compares well with the symmetrical cyclic urea 1 pioneered at
       DuPont Merck.
 DE    Binding Sites  Drug Resistance, Microbial  HIV Protease/METABOLISM  HIV
       Protease Inhibitors/*CHEMICAL SYNTHESIS/*PHARMACOLOGY  HIV-1/DRUG
       EFFECTS/*ENZYMOLOGY  Models, Molecular  JOURNAL ARTICLE

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