γ-Secretase Modulators : Can We Combine Potency with Safety?
Joint Authors
Gijsen, Harrie J. M.
Mercken, Marc
Source
International Journal of Alzheimer's Disease
Issue
Vol. 2012, Issue 2012 (31 Dec. 2012), pp.1-10, 10 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2012-12-17
Country of Publication
Egypt
No. of Pages
10
Main Subjects
Abstract EN
γ-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer’s approach.
γ-Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing.
As such, modulating γ-secretase may avoid some of the adverse effects observed with γ-secretase inhibitors.
Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds.
However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity.
The need for early and chronic dosing with GSMs will require high-safety margins.
This will be a challenge to achieve with the current, highly lipophilic GSMs.
We will demonstrate that by focusing on the drug-like properties of GSMs, a combination of high in vitro potency and reduced lipophilicity can be achieved and does result in better tolerated compounds.
The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safe in vivo.
American Psychological Association (APA)
Gijsen, Harrie J. M.& Mercken, Marc. 2012. γ-Secretase Modulators : Can We Combine Potency with Safety?. International Journal of Alzheimer's Disease،Vol. 2012, no. 2012, pp.1-10.
https://search.emarefa.net/detail/BIM-461209
Modern Language Association (MLA)
Gijsen, Harrie J. M.& Mercken, Marc. γ-Secretase Modulators : Can We Combine Potency with Safety?. International Journal of Alzheimer's Disease No. 2012 (2012), pp.1-10.
https://search.emarefa.net/detail/BIM-461209
American Medical Association (AMA)
Gijsen, Harrie J. M.& Mercken, Marc. γ-Secretase Modulators : Can We Combine Potency with Safety?. International Journal of Alzheimer's Disease. 2012. Vol. 2012, no. 2012, pp.1-10.
https://search.emarefa.net/detail/BIM-461209
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-461209