Document 0418
 DOCN  M9650418
 TI    Biological and biochemical anti-human immunodeficiency virus activity of
       UC 38, a new non-nucleoside reverse transcriptase inhibitor.
 DT    9605
 AU    McMahon JB; Buckheit RW Jr; Gulakowski RJ; Currens MJ; Vistica DT;
       Shoemaker RH; Stinson SF; Russell JD; Bader JP; Narayanan VL; Schultz
       RJ; Brouwer WG; Felauer EE; Boyd MR; Laboratory of Drug Discovery
       Research and Development, National; Cancer Institute, Frederick,
       Maryland, USA.
 SO    J Pharmacol Exp Ther. 1996 Jan;276(1):298-305. Unique Identifier :
       AIDSLINE MED/96135081
 AB    UC 38, a simple analog of oxathiin carboxanilide, UC 84, lacking the
       oxathiin ring, was found to be a potent inhibitor of human
       immunodeficiency virus (HIV)-1-induced cell killing and HIV replication
       in a variety of human cell lines, as well as in human peripheral blood
       lymphocytes and macrophages. UC 38 was active against a wide range of
       biologically diverse laboratory and clinical strains of HIV-1. However,
       UC 38 was inactive against HIV-2 and both nevirapine- and
       pyridinone-resistant strains of HIV-1. UC 38 selectively inhibited HIV-1
       reverse transcriptase (RT), but not HIV-2 RT. Combination of UC 38 with
       3'-azido-3'-deoxythymidine synergistically inhibited HIV-induced cell
       killing. An HIV-1 isolate resistant to UC 38 was selected in cell
       culture, and the mutations in the RT nucleotide sequences were
       determined. Comparison with the wild-type RT sequence revealed an amino
       acid change at position 181 (Tyr to Cys). The UC 38-resistant virus was
       found to be cross-resistant to a variety of structurally diverse
       non-nucleoside RT inhibitors. UC 38 was susceptible to rapid degradation
       in vitro and in vivo; yet, nontoxic in vivo concentrations of UC 38
       many-fold in excess of the in vitro effective concentrations could be
       achieved and maintained after s.c. or p.o. administration in hamsters.
       These results establish UC 38 as a new chemotype within the general
       class of HIV-1-specific RT inhibitors. The favorable physical
       characteristics, lack of toxicity, potency and bioavailability of UC 38
       may make it a candidate for combination chemotherapy of acquired immune
       deficiency syndrome.
 DE    Animal  Antiviral Agents/*PHARMACOLOGY/PHARMACOKINETICS
       Benzoates/*PHARMACOLOGY/PHARMACOKINETICS  Biological Availability
       Carboxin/ANALOGS & DERIVATIVES/PHARMACOLOGY/PHARMACOKINETICS
       Comparative Study  Drug Administration Schedule  Drug Resistance,
       Microbial  Drug Stability  Drug Synergism  DNA Mutational Analysis  DNA,
       Viral/ANALYSIS/GENETICS  Hamsters  Human  HIV-1/*DRUG EFFECTS/ENZYMOLOGY
       Male  Mice  Microbial Sensitivity Tests  Rats  Reverse Transcriptase
       Inhibitors/*PHARMACOLOGY/PHARMACOKINETICS  RNA-Directed DNA
       Polymerase/*DRUG EFFECTS  Thiocarbamates/*PHARMACOLOGY/PHARMACOKINETICS
       Zidovudine/PHARMACOLOGY  JOURNAL ARTICLE

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