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Design and synthesis of potent and selective BACE-1 inhibitors
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Bertil Samuelsson)
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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2010 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 4, 1458-1464 p.Article in journal (Refereed) Published
Abstract [en]

Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.

Place, publisher, year, edition, pages
American Chemical Society , 2010. Vol. 53, no 4, 1458-1464 p.
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-29748DOI: 10.1021/jm901168fISI: 000274581200004OAI: oai:DiVA.org:su-29748DiVA: diva2:235025
Available from: 2009-09-11 Created: 2009-09-11 Last updated: 2011-11-23Bibliographically approved
In thesis
1. Design and Synthesis of BACE-1 Inhibitors: Novel Compounds Targeting an Aspartic Protease Important in the Pathogenesis of Alzheimer’s Disease
Open this publication in new window or tab >>Design and Synthesis of BACE-1 Inhibitors: Novel Compounds Targeting an Aspartic Protease Important in the Pathogenesis of Alzheimer’s Disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the design and synthesis of protease inhibitors targeting the aspartic protease BACE-1 (β-site APP cleaving enzyme-1), an enzyme important in the pathogenesis of Alzheimer’s disease. The inhibitors are evaluated with respect to inhibition data, in a structure-activity relationship part.

Alzheimer’s disease is a disabling, progressive and ultimately fatal form of dementia afflicting approximately 40 percent of the population over 80 years, with over 30 million people suffering from Alzheimer’s disease worldwide. This makes Alzheimer’s disease the most common form of dementia. The identification of the amyloid-β peptide (Aβ) as the main constituent of extracellular plaques, which characterize Alzheimer’s disease, suggests that Aβ plays a vital role in the pathology of Alzheimer’s disease. The formation of Aβ occurs when amyloid-β precursor protein (APP) is cleaved by β-secretase (BACE-1) and γ-secretase, which differ in length by 39-42 amino acids. This suggests that β-secretase is a suitable target for the development of therapeutics against Alzheimer’s disease.

The synthetic work of this thesis comprises development of BACE-1 inhibitors containing a hydroxyethylene (HE) central core transition state isostere. The target molecules were readily synthesized from chiral carbohydrate starting materials. Highly potent inhibitors were produced by varying the substituents coupled to the HE central core. Selecting an aryloxymethyl P1 side-chain and a methoxy P1’ side-chain resulted in exceptionally potent BACE-1 inhibitors that also exhibit high selectivity over cathepsin D. In a further development, the ether oxygen linkage in the P1 side-chain was removed, resulting in a carba analogue, providing improved potency in a cell-based assay.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2009. 56 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29755 (URN)978-91-7155-933-3 (ISBN)
Public defence
2009-10-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Swedish)
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Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 2: Submitted. Paper 3: Manuscript. Paper 4: Submitted.Available from: 2009-09-24 Created: 2009-09-11 Last updated: 2010-06-02Bibliographically approved

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