       Document 0121
 DOCN  M9630121
 TI    Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse
       transcriptase inhibitors. 1. Synthesis and basic structure-activity
       relationship studies of PETT analogs.
 DT    9603
 AU    Bell FW; Cantrell AS; Hogberg M; Jaskunas SR; Johansson NG; Jordan CL;
       Kinnick MD; Lind P; Morin JM Jr; Noreen R; et al; Lilly Research
       Laboratories, Eli Lilly and Company, Lilly; Corporate Center,
       Indianapolis, Indiana 46285, USA.
 SO    J Med Chem. 1995 Dec 8;38(25):4929-36. Unique Identifier : AIDSLINE
       MED/96105435
 AB    A novel series of potent specific HIV-1 inhibitory compounds is
       described. The lead compound in the series,
       N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using
       rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound
       1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in
       cell culture is > 380 microM. The chemical structure-activity
       relationship (SAR) was developed by notionally dividing the lead
       compound in four quadrants. The SAR strategy had two phases. The first
       phase involved optimization of antiviral activity through independent
       variation of quadrants 1-4. The second phase involved the preparation of
       hybrid structures combining the best of these substituents. Further SAR
       studies and pharmacokinetic considerations led to the identification of
       N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a
       candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with
       an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.
 DE    Animal  Antiviral Agents/*CHEMICAL SYNTHESIS/PHARMACOLOGY  Cell Line
       Human  HIV-1/*DRUG EFFECTS/ENZYMOLOGY  Isothiocyanates/CHEMICAL
       SYNTHESIS  Rats  Reverse Transcriptase Inhibitors/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  Structure-Activity Relationship
       Thiazoles/CHEMICAL SYNTHESIS/*PHARMACOLOGY  Thiourea/*ANALOGS &
       DERIVATIVES/CHEMICAL SYNTHESIS/PHARMACOLOGY  JOURNAL ARTICLE

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

