Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue
2021
Аутори:
Saretz, StefanBasset, Gabriele
Useini, Liridona
Laube, Markus
Pietzsch, Jens
Drača, Dijana
Maksimović-Ivanić, Danijela
Trambauer, Johannes
Steiner, Harald
Hey-Hawkins, Evamarie
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
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.
Кључне речи:
Alzheimer; Amyloid-β (Aβ) peptide; Carborane; Flurbiprofen; Phenyl mimetic; Small molecule; γ-secretase modulator (GSM)Извор:
Molecules, 2021, 26, 10, 2843-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
DOI: 10.3390/molecules26102843
ISSN: 1420-3049
PubMed: 34064783
WoS: 000655054800001
Scopus: 2-s2.0-85106616220
URI
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151329/https://radar.ibiss.bg.ac.rs/handle/123456789/4250