Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Markus Laube
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraße 400, D-01328 Dresden, Germany
Jens Pietzsch
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraße 400, D-01328 Dresden, Germany
Dijana Drača
Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bul. Despota Stefana 142, 11060 Belgrade, Serbia
Danijela Maksimović-Ivanić
Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bul. Despota Stefana 142, 11060 Belgrade, Serbia
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.
