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  3. DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

  • Sci Rep. 2018 Feb 12;8(1):2859. doi: 10.1038/s41598-018-20984-z.
Fernanda Neumann 1,  Stéphanie Gourdain 1,  Christelle Albac 2,  Alain D Dekker 2 3,  Linh Chi Bui 4,  Julien Dairou 5,  Isabelle Schmitz-Afonso 1,  Nathalie Hue 1,  Fernando Rodrigues-Lima 4,  Jean M Delabar 2,  Marie-Claude Potier 2,  Jean-Pierre Le Caër 1,  David Touboul 1,  Benoît Delatour 2,  Kevin Cariou 1,  Robert H Dodd 6
Affiliations

Affiliations

  • 1 Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, Avenue de la Terrasse, 91198, Gif-sur-Yvette, France.
  • 2 Sorbonne Universités, Université Pierre et Marie Curie (UPMC), Université Paris 06, Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique (CNRS) Unités de Recherche U75, U1127, U7225, and Institut du Cerveau et de la Moelle Epinière (ICM), 75013, Paris, France.
  • 3 Department of Neurology, University of Groningen, University Medical Center Groningen (UMCG), Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
  • 4 Université Paris Diderot, Sorbonne Paris Cité, Unité BFA, CNRS UMR 8251, 75013, Paris, France.
  • 5 UMR 8601 CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes-Sorbonne Paris Cité, 75270, Paris, France.
  • 6 Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, Avenue de la Terrasse, 91198, Gif-sur-Yvette, France. robert.dodd@cnrs.fr.
PMID: 29434250 DOI: 10.1038/s41598-018-20984-z
Abstract

Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.

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