Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles

C. Anne Higley, Richard G. Wilde, Thomas P. Maduskuie, Alexander L. Johnson, Pennio Pennev, Jeffrey T. Billheimer, Candy S. Robinson, Peter J. Gillies, Ruth R. Wexler

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N′-{2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2-yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.

Original languageEnglish (US)
Pages (from-to)3511-3522
Number of pages12
JournalJournal of medicinal chemistry
Volume37
Issue number21
DOIs
StatePublished - Oct 1 1994
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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