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  • 1.
    Sandgren, Veronica
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Design and Synthesis of Inhibitors Targeting BACE-1, an Aspartic Protease Involved in the Pathogenesis of Alzheimer’s Disease2012Doctoral 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.

    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, p. 1-15Article 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, p. 4377-4389Article 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
    Keywords
    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
  • 2.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Agback, Tatiana
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Johansson, Per-Ola
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Lindberg, Jimmy
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Belda, Oscar
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes2012In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 29, no 14, p. 4377-4389Article in journal (Refereed)
    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.

  • 3.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Belda, Oscar
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Johansson, Per-Ola
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Design and synthesis of novel macrocyclic BACE-1 inhibitorsManuscript (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.

  • 4.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Belda, Oscar
    Medivir AB, Huddinge, Sweden.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lindberg, Jimmy
    Medivir AB, Huddinge, Sweden.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors2015In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 9, p. 13-26Article in journal (Refereed)
    Abstract [en]

    A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.

  • 5.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents2013In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 7, p. 1-15Article in journal (Refereed)
    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.

  • 6.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 positionManuscript (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.

1 - 6 of 6
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