Imidazo[2,1- b ]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor - Université de Montpellier Accéder directement au contenu
Article Dans Une Revue ACS Medicinal Chemistry Letters Année : 2018

Imidazo[2,1- b ]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor

Michael Christodoulou
  • Fonction : Auteur
Federico Dapiaggi
  • Fonction : Auteur
Francesca Ghiringhelli
  • Fonction : Auteur
Stefano Pieraccini
  • Fonction : Auteur
Maurizio Sironi
  • Fonction : Auteur
Marianna Lucafò
  • Fonction : Auteur
Debora Curci
  • Fonction : Auteur
Giuliana Decorti
  • Fonction : Auteur
  • PersonId : 881985
Gabriele Stocco
  • Fonction : Auteur
Chandra Sekhar Chirumamilla
  • Fonction : Auteur
Wim Vanden Berghe
  • Fonction : Auteur
Benoît Michel
Alain Burger
Egle Beccalli
  • Fonction : Auteur
Daniele Passarella
  • Fonction : Auteur
Nadine Martinet
  • Fonction : Auteur
  • PersonId : 918328

Résumé

Glucocorticoid receptor (GCR) transactivation reporter gene assays were used as an initial high-throughput screening on a diversified library of 1200 compounds for their evaluation as GCR antagonists. A class of imidazo[2,1-b]benzothiazole and imidazo[2,1-b]benzoimidazole derivatives were identified for their ability to modulate GCR transactivation and anti-inflammatory transrepression effects utilizing GCR and NF-κB specific reporter gene assays. Modeling studies on the crystallographic structure of the GCR ligand binding domain provided three new analogues bearing the tetrahydroimidazo[2,1-b]benzothiazole scaffold able to antagonize the GCR in the presence of dexamethasone (DEX) and also defined their putative binding into the GCR structure. Both mRNA level measures of GCR itself and its target gene GILZ, on cells treated with the new analogues, showed a GCR transactivation inhibition, thus suggesting a potential allosteric inhibition of the GCR.

Dates et versions

hal-02285732 , version 1 (13-09-2019)

Identifiants

Citer

Michael Christodoulou, Federico Dapiaggi, Francesca Ghiringhelli, Stefano Pieraccini, Maurizio Sironi, et al.. Imidazo[2,1- b ]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor. ACS Medicinal Chemistry Letters, 2018, 9 (4), pp.339-344. ⟨10.1021/acsmedchemlett.7b00527⟩. ⟨hal-02285732⟩
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