TY  - JOUR
AU  - Saretz, Stefan
AU  - Basset, Gabriele
AU  - Useini, Liridona
AU  - Laube, Markus
AU  - Pietzsch, Jens
AU  - Drača, Dijana
AU  - Maksimović-Ivanić, Danijela
AU  - Trambauer, Johannes
AU  - Steiner, Harald
AU  - Hey-Hawkins, Evamarie
PY  - 2021
UR  - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151329/
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4250
AB  - 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.
PB  - MDPI AG
T2  - Molecules
T1  - Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue
IS  - 10
VL  - 26
DO  - 10.3390/molecules26102843
SP  - 2843
ER  - 

@article{
author = "Saretz, Stefan and Basset, Gabriele and Useini, Liridona and Laube, Markus and Pietzsch, Jens and Drača, Dijana and Maksimović-Ivanić, Danijela and Trambauer, Johannes and Steiner, Harald and Hey-Hawkins, Evamarie",
year = "2021",
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-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.",
publisher = "MDPI AG",
journal = "Molecules",
title = "Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue",
number = "10",
volume = "26",
doi = "10.3390/molecules26102843",
pages = "2843"
}

Saretz, S., Basset, G., Useini, L., Laube, M., Pietzsch, J., Drača, D., Maksimović-Ivanić, D., Trambauer, J., Steiner, H.,& Hey-Hawkins, E.. (2021). Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue. in Molecules
MDPI AG., 26(10), 2843.
https://doi.org/10.3390/molecules26102843

Saretz S, Basset G, Useini L, Laube M, Pietzsch J, Drača D, Maksimović-Ivanić D, Trambauer J, Steiner H, Hey-Hawkins E. Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue. in Molecules. 2021;26(10):2843.
doi:10.3390/molecules26102843 .

Saretz, Stefan, Basset, Gabriele, Useini, Liridona, Laube, Markus, Pietzsch, Jens, Drača, Dijana, Maksimović-Ivanić, Danijela, Trambauer, Johannes, Steiner, Harald, Hey-Hawkins, Evamarie, "Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue" in Molecules, 26, no. 10 (2021):2843,
https://doi.org/10.3390/molecules26102843 . .