Molecules (May 2021)

Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue

  • Stefan Saretz,
  • Gabriele Basset,
  • Liridona Useini,
  • Markus Laube,
  • Jens Pietzsch,
  • Dijana Drača,
  • Danijela Maksimović-Ivanić,
  • Johannes Trambauer,
  • Harald Steiner,
  • Evamarie Hey-Hawkins

DOI
https://doi.org/10.3390/molecules26102843
Journal volume & issue
Vol. 26, no. 10
p. 2843

Abstract

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All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.

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