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Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A novel hydroxyethylene (HE) core structure with an O-methyl group in the P1´ position, previously reported by our group, has been further evaluated by introducing a substituted cyclopentane moiety in the P2 position. Results from earlier published work suggest that inhibitors containing the novel O-methyl HE core may result in inhibitors displaying promising potency against BACE-1 as well as selectivity towards cathepsin D. Furthermore, there is a general need for new and improved moieties in the P2 position for many BACE-1 inhibitors, e.g., the widely used substituted P2 isophthalamide structure often gives rise to inhibitors suffering from poor pharmacokinetics, including insufficient blood-brain barrier permeability. Different stereoisomers of the P2 cyclopentane moieties and a selection of P3 substituents have been examined. In addition, a macrocyclization study linking the P1 and P3 moieties was performed and biological results are discussed.

National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76170OAI: oai:DiVA.org:liu-76170DiVA: diva2:512913
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved
In thesis
1. Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease
Open this publication in new window or tab >>Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is the most common form of dementia, occurring in an estimated 24 million people worldwide. Accumulation of amyloid-b peptides leads to development of plaques in the brain, which eventually stimulates hyperphosphorylation of tau proteins leading to tangles. This is believed to play a crucial role in the pathology of AD. The amyloid-b peptides are formed when the amyloid precursor protein (APP) is cleaved first by the human aspartic protease BACE-1 and then by the protease g-secretase. BACE-1 catalyzes the ratelimiting step in this sequence, and hence it has emerged as an important therapeutic drug target.

The research reported in this thesis is focused on the design and synthesis of BACE-1 inhibitors, where the synthetic work involves development of both acyclic and cyclic inhibitors. Initially, a series of linear inhibitors incorporating substituted cyclopentanes in the P2 position were synthesized and evaluated in an attempt to find a replacement for the widely used isophthalamide moiety, and this endeavor generated an inhibitor with activity in the nanomolar range. In the second study, a series of hydroxyethylene-based inhibitors with extended P1 substituents was synthesized and evaluated, which resulted in several truncated inhibitors also with activities in the nanomolar range. The third investigation targeted a series of P1-P3-linked hydroxyethylamine-based macrocyclic inhibitors and provided several highly potent compounds, however it did not deliver high cell permeability inhibitors. In addition, two inhibitors were co-crystallized with BACE-1 to provide X-ray crystal structures, which enabled analysis of the binding properties of these inhibitors. In the final study, the P2/P3 macrocyclic amide moiety and the P1-P3 ether oxygen bridge from the previous work were replaced with a keto functionality and a carbon, respectively, in an attempt to improve the permeability properties whilst maintaining the beneficial potencies of this class of macrocyclic inhibitors. The compounds synthesized did indeed display enhanced cell permeability properties, but this approach resulted in decreased potency.

In short, this thesis presents several novel BACE-1 inhibitors, discusses the synthetic strategies, and reports biological data on the target compounds.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 78 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1436
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76174 (URN)978-91-7519-933-7 (ISBN)
Public defence
2012-04-27, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-04-02Bibliographically approved

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Sandgren, VeronicaKvarnström, IngemarDahlgren, Anders

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