Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

M. Meyer, Sebastien Foulquier, F. Dupuis, Stéphane Flament, L. Grimaud, Daniel Henrion, I. Lartaud, Gérald Monard, Isabelle Grillier-Vuissoz, Michel Boisbrun

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets,
called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-g (PPAR-g). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-g and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-g activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.
Original languageEnglish
Pages (from-to)334-352
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Volume158
DOIs
Publication statusPublished - 5 Oct 2018

Keywords

  • Designed multiple ligands
  • AT(1)
  • PPAR-gamma
  • lmidazole
  • Triazole
  • Chromane
  • PPAR-GAMMA
  • DRUG DISCOVERY
  • ALZHEIMERS-DISEASE
  • METABOLIC SYNDROME
  • 4-THIAZOLIDINONE DERIVATIVES
  • ANTIPROLIFERATIVE ACTIVITY
  • HIGHLY EFFICIENT
  • DUAL ACTIVITY
  • AGONISTS
  • ANTAGONISTS

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