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Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Bertil Samuelsson)
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Bertil Samuelsson)
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Hans Adolfsson)
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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: urn:nbn:se:su:diva-29558OAI: oai:DiVA.org:su-29558DiVA: diva2:234154
Available from: 2009-09-06 Created: 2009-09-06 Last updated: 2010-06-02Bibliographically 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)
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
2. Design and Synthesis of Inhibitors Targeting the Aspartic Proteases HIV-1 PR and BACE-1
Open this publication in new window or tab >>Design and Synthesis of Inhibitors Targeting the Aspartic Proteases HIV-1 PR and BACE-1
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis of molecules designed for inhibition of two aspartic proteases, viral HIV-1 PR and human BACE-1. It also reports on the structure activity relationships of the targeted enzyme inhibitors.

It is estimated that currently 33 million people are infected with HIV, the causative agent of AIDS. The virus targets T-lymphocytes and macrophages of the human immune system. The HIV-1 PR plays an important role in the viral replication, and by inhibiting the enzyme the disease progression can be slowed down or even halted.

Herein is reported the design and synthesis of a series of HIV-1 PR inhibitors with novel P2 substituents of which several inhibit the enzyme in the nanomolar range. The aim of the second work was to further develop the inhibitors by the introduction of fluorine. Several attempts were performed to fluorinate different P2-substituents.

Alzheimer’s disease (AD) is neurodegenerative, progressive and fatal disorder of the brain. It is associated with accumulation of plaques and tangles that cause impairment and functional decline of brain tissue which result in loss of memory and cognition. The plaques are mainly constituted of amyloid-β peptides that are generated in two steps from the amyloid precursor protein (APP). The cleavage sequence is initiated by the aspartic protease BACE-1, which makes the enzyme a key target in the effort of finding a therapy that aim to slow down the progression of AD.

Herein are enclosed the development of two series of potent BACE-1 inhibitors. In the first work a synthetic strategy was developed to truncate a previously reported hydroxyethylene core structure in order to generate more drug-like inhibitors. This generated a series of truncated inhibitors where two amide bonds have been replaced with an ether - or alternatively a secondary amine linkage. A number of these inhibitors show potency against BACE-1. In the second part of the work the aim was investigate the effect of alterations in the P1 position. Five scaffolds with new P1 substituents were designed, synthesized and coupled with two different P2-P3 substituents. This resulted in a series of potent inhibitors that inhibit BACE-1 in the nanomolar range.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2009. 73 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29773 (URN)978-91-7155-940-1 (ISBN)
Public defence
2009-10-14, 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.Available from: 2009-09-22 Created: 2009-09-14 Last updated: 2009-09-15Bibliographically approved

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