Document 0447
 DOCN  M9590447
 TI    Suppression of the breakthrough of human immunodeficiency virus type 1
       (HIV-1) in cell culture by thiocarboxanilide derivatives when used
       individually or in combination with other HIV-1-specific inhibitors
       (i.e., TSAO derivatives).
 DT    9509
 AU    Balzarini J; Perez-Perez MJ; Velazquez S; San-Felix A; Camarasa MJ; De
       Clercq E; Karlsson A; Rega Institute for Medical Research, Katholieke
       Universiteit; Leuven, Belgium.
 SO    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5470-4. Unique Identifier :
       AIDSLINE MED/95296332
 AB    Five structurally related thiophene and furane analogues of the oxathiin
       carboxanilide derivative NSC 615985 (UC84) (designated UC10, UC68, UC81,
       UC42, and UC16) were identified as potent inhibitors of HIV-1
       replication in cell culture and HIV-1 reverse transcriptase activity.
       These compounds were markedly active against a series of mutant HIV-1
       strains, containing the Leu-100-->Ile, Val-106-->Ala, Glu-138-->Lys, or
       Tyr-181-->Cys mutations in their reverse transcriptase. However, the
       thiocarboxanilide derivatives selected for mutations at amino acid
       positions 100 (Leu-->Ile), 101 (Lys-->Ile/Glu), 103 (Lys-->Thr/Asp) and
       141 (Gly-->Glu) in the HIV-1 reverse transcriptase. The compounds
       completely suppressed HIV-1 replication and prevented the emergence of
       resistant virus strains when used at 1.3-6.6 microM--that is, 10- to
       25-fold lower than the concentration required for nevirapine and
       bis(heteroaryl)piperazine (BHAP) U90152 to do so. If UC42 was combined
       with the [2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5-(4-amino-1,2-
       oxathiole-2,2-dioxide)]-beta-D-pentofuranosyl (TSAO) derivative of
       N3-methylthymine (TSAO-m3T), virus breakthrough could be prevented for a
       much longer time, and at much lower concentrations, than if the
       compounds were used individually. Virus breakthrough could be suppressed
       for even longer, and at lower drug concentrations, if BHAP was added to
       the combination of UC42 with TSAO-m3T, which points to the feasibility
       of two- or three-drug combinations in preventing virus breakthrough and
       resistance development.
 DE    Antiviral Agents/CHEMISTRY/*PHARMACOLOGY  Base Sequence
       Carboxin/*ANALOGS & DERIVATIVES/CHEMISTRY/PHARMACOLOGY  Cell Line  Drug
       Antagonism  DNA Primers  Human  HIV-1/*DRUG
       EFFECTS/ENZYMOLOGY/GENETICS/PHYSIOLOGY  Indoles/PHARMACOLOGY  Molecular
       Sequence Data  Mutation  Piperazines/PHARMACOLOGY  Reverse
       Transcriptase/ANTAGONISTS & INHIB  Spiro Compounds/PHARMACOLOGY
       Support, Non-U.S. Gov't  Thymidine/ANALOGS & DERIVATIVES/PHARMACOLOGY
       JOURNAL ARTICLE

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