Imidazolylbenzopyrane derivatives: A new class of acyl-coa: Cholesterol acyltranferase (ACAT) inhibitors

Daniele Fancelli, Augusto Chiari, Paolo Cozzi, Pierpaolo Lovisolo, Dino Severino, Giancarlo Ghiselli

Research output: Contribution to journalArticle

Abstract

Inhibitors of the enzyme Acyl-CoA: Cholesterol Acyltransferase are regarded as potentially useful agents in the treatment of hypercholesterolemia and atherosclerosis. We report here a novel series of 2, 6-disubstituted-3-imidazolylbenzopyrane derivatives with significant in vitro ACAT inhibitory activity (IC50 range 0.05-0.5 μM). Compounds of this series such as 26 are examples of a new, structurally distinct class of potent ACAT inhibitors with high specificity for the aortic subtype of the enzyme. The structure-activity relationships of the 3-imidazolylbenzopyrane ACAT inhibitors were investigated by systematic manipulation of two regions of the parent compound 1 and the inhibitory activity resulted linked to the substituent in position 6 of the benzopyrane ring and modulated by the size of lipophilic substituents in position 2. Investigation of the mechanism of the inhibitory effect leads to the conclusion that these compounds act in a non-competitive fashion.

Original languageEnglish
Pages (from-to)159-172
Number of pages14
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume8
Issue number3
DOIs
Publication statusPublished - 1994

Keywords

  • 2,6-disubstituted-3-imidazolyl-benzopyranes
  • ACAT
  • Acyl-CoA
  • Atherosclerosis
  • Cholesterol Acyltransferase
  • Inhibition

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Biochemistry
  • Molecular Medicine

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