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Design and Synthesis of BACE-1 Inhibitors: Novel Compounds Targeting an Aspartic Protease Important in the Pathogenesis of Alzheimer’s Disease
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Bertil Samuelsson)
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: urn:nbn:se:su:diva-29755ISBN: 978-91-7155-933-3 (print)OAI: oai:DiVA.org:su-29755DiVA: diva2:235029
Public defence
2009-10-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Swedish)
Opponent
Supervisors
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
List of papers
1. Design and synthesis of potent and selective BACE-1 inhibitors
Open this publication in new window or tab >>Design and synthesis of potent and selective BACE-1 inhibitors
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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
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29748 (URN)10.1021/jm901168f (DOI)000274581200004 ()
Available from: 2009-09-11 Created: 2009-09-11 Last updated: 2011-11-23Bibliographically approved
2. Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core
Open this publication in new window or tab >>Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core
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2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 4, 1711-1723 p.Article in journal (Refereed) Published
Abstract [en]

In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

Place, publisher, year, edition, pages
Elsevier Ltd., 2010
Keyword
Alzhemier’s Disease, BACE-1 inhibitors, Hydroxyethylene (HE) isostere, Aminoethylene (AE) isostere, P1’ modifications, Peptidomimetics
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29754 (URN)10.1016/j.bmc.2009.12.051 (DOI)000274425500036 ()
Available from: 2009-09-11 Created: 2009-09-11 Last updated: 2011-11-23Bibliographically approved
3. Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
Open this publication in new window or tab >>Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.

National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29558 (URN)
Available from: 2009-09-06 Created: 2009-09-06 Last updated: 2010-06-02Bibliographically approved
4. P2’-truncated BACE-1 inhibitors with a novel hydroxethylene-like core
Open this publication in new window or tab >>P2’-truncated BACE-1 inhibitors with a novel hydroxethylene-like core
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2010 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, no 2, 542-554 p.Article in journal (Refereed) Published
Abstract [en]

Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2’ amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-1 IC50 value of 140 nM. The synthesis of these BACE-1 inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.

Place, publisher, year, edition, pages
Elsevier Masson SAS, 2010
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29559 (URN)10.1016/j.ejmech.2009.10.041 (DOI)000274773300016 ()
Available from: 2009-09-06 Created: 2009-09-06 Last updated: 2011-11-23Bibliographically approved

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