       Document 0028
 DOCN  M9610028
 TI    The PETT series, a new class of potent nonnucleoside inhibitors of human
       immunodeficiency virus type 1 reverse transcriptase.
 DT    9601
 AU    Ahgren C; Backro K; Bell FW; Cantrell AS; Clemens M; Colacino JM; Deeter
       JB; Engelhardt JA; Hogberg M; Jaskunas SR; et al; Lilly Research
       Laboratories, Eli Lilly and Company, Indianapolis,; Indiana, USA.
 SO    Antimicrob Agents Chemother. 1995 Jun;39(6):1329-35. Unique Identifier :
       AIDSLINE MED/96012195
 AB    To identify the minimal structural elements necessary for biological
       activity, the rigid tricyclic nucleus of the known human
       immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT)
       inhibitor tetrahydroimidazobenzodiazepinthione was subjected to
       systematic bond disconnection to obtain simpler structures. A rational
       selection and testing of modeled analogs containing these potential
       pharmacophoric moieties led to the discovery of a new series of
       nonnucleoside inhibitors of RT. The lead compound of this new PETT
       series of nonnucleoside RT inhibitors,
       N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to
       inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell
       culture at micromolar concentrations. This derivative was also found to
       inhibit HIV-1 RT. Through an integrated effort involving synthesis and
       molecular modeling, compounds with nanomolar potency against HIV-1 in
       cell culture were developed. In these studies, LY300046-HCl was
       identified as a potent nonnucleoside inhibitor of HIV-1 RT possessing
       favorable pharmacokinetic properties.
 DE    Animal  Antiviral Agents/PHARMACOLOGY  Base Sequence
       Benzodiazepines/CHEMISTRY  Brain/METABOLISM  Cattle  Cells, Cultured
       Comparative Study  Drug Resistance, Microbial  DNA Polymerases/DRUG
       EFFECTS/METABOLISM  Human  HIV-1/*DRUG EFFECTS  Imidazoles/CHEMISTRY
       Intercalating Agents/*PHARMACOLOGY  Male  Molecular Sequence Data
       Pyridines/CHEMICAL SYNTHESIS/PHARMACOLOGY/PHARMACOKINETICS  Rats  Rats,
       Inbred F344  *Reverse Transcriptase Inhibitors  Structure-Activity
       Relationship  Support, U.S. Gov't, P.H.S.  Thiazoles/CHEMICAL
       SYNTHESIS/*PHARMACOLOGY  Thiourea/ANALOGS & DERIVATIVES/CHEMICAL
       SYNTHESIS/PHARMACOLOGY  Triazoles/*PHARMACOLOGY  JOURNAL ARTICLE

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

