       Document 0613
 DOCN  M9630613
 TI    SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1
       proteinase inhibitor containing the 2-aminobenzylstatine moiety.
 DT    9603
 AU    Billich A; Fricker G; Muller I; Donatsch P; Ettmayer P; Gstach H; Lehr
       P; Peichl P; Scholz D; Rosenwirth B; Sandoz Research Institute, Vienna,
       Austria.
 SO    Antimicrob Agents Chemother. 1995 Jul;39(7):1406-13. Unique Identifier :
       AIDSLINE MED/96104872
 AB    A series of inhibitors of human immunodeficiency virus type 1 (HIV-1)
       proteinase containing the 2-aralkyl-amino-substituted statine moiety as
       a novel transition-state analog was synthesized, with the aim to obtain
       compounds which combine anti-HIV potency with oral bioavailability. The
       reduced-size 2-aminobenzylstatine derivative SDZ PRI 053, which contains
       2-(S)-amino-3-(R)-hydroxyindane in place of an amino acid amide, is a
       potent and orally bioavailable inhibitor of HIV-1 replication. The
       antiviral activity of SDZ PRI 053 was demonstrated in various cell
       lines, in primary lymphocytes, and in primary monocytes, against
       laboratory strains as well as clinical HIV-1 isolates (50% effective
       dose = 0.028 to 0.15 microM). Cell proliferation was impaired only at
       100- to 300-fold-higher concentrations. The mechanism of antiviral
       action of the proteinase inhibitor SDZ PRI 0.53 was demonstrated to be
       inhibition of gag precursor protein processing. The finding that the
       inhibitory potency of SDZ PRI 053 in chronic virus infection, determined
       by p24 release, was considerably lower than that in de novo infection
       may be explained by the fact that the virus particles produced in the
       presence of SDZ PRI 053 are about 50-fold less infectious than those
       from untreated cultures. Upon intravenous administration, half-lives in
       blood of 100 and 32 min in mice and rats, respectively, were measured.
       Oral bioavailability of SDZ PRI 053 in rodents was 20 to 60%, depending
       on the dose.(ABSTRACT TRUNCATED AT 250 WORDS)
 DE    Administration, Oral  Amino Acid Sequence  Animal  Biological
       Availability  Blood Proteins/METABOLISM  Cell Line  Comparative Study
       Dogs  Female  Gene Products, gag/ANTAGONISTS & INHIB/METABOLISM  Human
       HIV Protease Inhibitors/CHEMICAL SYNTHESIS/*PHARMACOLOGY/
       PHARMACOKINETICS  HIV-1/DRUG EFFECTS/ENZYMOLOGY/PHYSIOLOGY
       Indans/BLOOD/*PHARMACOLOGY/PHARMACOKINETICS  Mice  Mice, Inbred BALB C
       Molecular Sequence Data  Protein Binding  Rats  Rats, Wistar
       Structure-Activity Relationship  Virus Replication/DRUG EFFECTS  JOURNAL
       ARTICLE

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

