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

Neumann, F., Gourdain, S., Albac, C., Dekker, A. D., Bui, L. C., Dairou, J., Schmitz-Afonso, I., Hue, N., Rodrigues-Lima, F., Delabar, J. M., Potier, M-C., Le Caer, J-P., Touboul, D., Delatour, B., Cariou, K. & Dodd, R. H., 12-Feb-2018, In : Scientific Reports. 8, 12 p., 2859.

Research output: Contribution to journalArticleAcademicpeer-review

  • Fernanda Neumann
  • Stephanie Gourdain
  • Christelle Albac
  • Alain D. Dekker
  • Linh Chi Bui
  • Julien Dairou
  • Isabelle Schmitz-Afonso
  • Nathalie Hue
  • Fernando Rodrigues-Lima
  • Jean M. Delabar
  • Marie-Claude Potier
  • Jean-Pierre Le Caer
  • David Touboul
  • Benoit Delatour
  • Kevin Cariou
  • Robert H. Dodd

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.

Original languageEnglish
Article number2859
Number of pages12
JournalScientific Reports
Volume8
Publication statusPublished - 12-Feb-2018

    Keywords

  • ENVIRONMENTAL NEUROTOXIN ANNONACIN, PROTEIN-KINASE INHIBITORS, ALZHEIMER-DISEASE, DUAL-SPECIFICITY, FUNCTIONAL-LINK, SYNDROME MICE, UPLC-MS/MS, DEFICITS, BRAIN, RAT

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