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Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
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: urn:nbn:se:liu:diva-76174ISBN: 978-91-7519-933-7 (print)OAI: oai:DiVA.org:liu-76174DiVA: diva2:512925
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
List of papers
1. Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position
Open this publication in new window or tab >>Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 position
(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:nbn:se:liu:diva-76170 (URN)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved
2. Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents
Open this publication in new window or tab >>Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents
2013 (English)In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 7, 1-15 p.Article in journal (Refereed) Published
Abstract [en]

Novel BACE-1 inhibitors with a hydroxyethylene central core have been  developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e., 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.

Place, publisher, year, edition, pages
Bussum, Netherlands: Bentham Open, 2013
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76171 (URN)10.2174/1874104501307010001 (DOI)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2017-12-07Bibliographically approved
3. Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
Open this publication in new window or tab >>Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes
Show others...
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
Keyword
Alzheimer’s disease; BACE-1 inhibition; Macrocycles; Hydroxyethylamine (HEA) isostere
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76172 (URN)10.1016/j.bmc.2012.05.039 (DOI)000305952500023 ()
Note

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: 2017-12-07Bibliographically approved
4. Design and synthesis of novel macrocyclic BACE-1 inhibitors
Open this publication in new window or tab >>Design and synthesis of novel macrocyclic BACE-1 inhibitors
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A series of arylketo-containing P1-P3 linked macrocyclic inhibitors was designed and synthesized and compared with a previously known and extensively used corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme and cell-based potencies. Several inhibitors displayed a substantial increase in Caco-2 cell-based permeability and notably also with retained potencies, showing that this approach might lead to centrally active BACE-1 inhibitors.

National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-76173 (URN)
Available from: 2012-03-29 Created: 2012-03-29 Last updated: 2012-03-29Bibliographically approved

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Sandgren, Veronica

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