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Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
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2012 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 29, no 14, 4377-4389 p.Article in journal (Refereed) Published
Abstract [en]

A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.

Place, publisher, year, edition, pages
Elsevier, 2012. Vol. 29, no 14, 4377-4389 p.
Keyword [en]
Alzheimer’s disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere
National Category
Natural Sciences
URN: urn:nbn:se:liu:diva-76172DOI: 10.1016/j.bmc.2012.05.039ISI: 000305952500023OAI: diva2:512918

On the day of the defence day the status of this article was Manuscript.

Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-09-18Bibliographically 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.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1436
National Category
Natural Sciences
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)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-04-02Bibliographically approved

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