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

Saretz, Stefan; Basset, Gabriele; Useini, Liridona; Laube, Markus; Pietzsch, Jens; Draca, Dijana; Maksimovic-Ivanic, Danijela; Trambauer, Johannes; Steiner, Harald und Hey-Hawkins, Evamarie (2021): Modulation of gamma-Secretase Activity by a Carborane-Based Flurbiprofen Analogue. In: Molecules, Bd. 26, Nr. 10, 2843

Abstract

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-beta (A beta) fragments in the brain by modulation of gamma-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 logD(7.4) value of 2.0. Furthermore, our analogue retained gamma-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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch