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Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 1, 145-155 p.Article in journal (Refereed) Published
Abstract [en]

Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

Place, publisher, year, edition, pages
2011. Vol. 19, no 1, 145-155 p.
Keyword [en]
α-Benzylnorstatine, α-Phenylnorstatine, Alzheimer's disease, BACE-1 inhibitors, tert-Hydroxyl, Transition state mimic
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-109026DOI: 10.1016/j.bmc.2010.11.042ISI: 000285724800014PubMedID: 21183353OAI: oai:DiVA.org:uu-109026DiVA: diva2:242288
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Design and Synthesis of Aspartic and Serine Protease Inhibitors: Targeting the BACE-1 and the HCV NS3 Protease
Open this publication in new window or tab >>Design and Synthesis of Aspartic and Serine Protease Inhibitors: Targeting the BACE-1 and the HCV NS3 Protease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes work done to design and synthesize protease inhibitors, with the intention of developing therapeutic agents for Alzheimer’s disease (AD) and the chronic liver condition caused by infection of the hepatitis C virus (HCV). AD is the most common form of dementia, and HCV infection is the primary reason for liver transplantation in industrialized countries. Today, these two illnesses affect 24 and 170 million people, respectively. It has been shown that the human aspartic protease BACE-1 plays an important role in the development of AD, and thus inhibition of BACE-1 may offer a way to improve the quality of life of individuals afflicted with the disease. Furthermore, it is known that the serine protease NS3 is a vital component in the replication of HCV.

Several novel potent BACE-1 inhibitors encompassing different transition state mimics were prepared. First, a hydroxyethylene moiety encompassing a secondary hydroxyl group was evaluated as a transition state analogue, producing inhibitors in the low nanomolar range. Various tertiary hydroxyl isosteres were also investigated as the central core, with the aim of shielding the pivotal hydroxyl group. These transition state isosteres consisted of tertiary hydroxyl analogues of previously used secondary hydroxyl containing norstatine, statine, and hydroxyethylamine isosteres. Several tertiary hydroxyl-containing inhibitors were found to be active in the low micromolar range. In addition, two inhibitors were co-crystallized with the BACE-1 enzyme to provide X-ray crystal structures, which furnished valuable binding information for further design of improved BACE-1 inhibitors.

The goal in the HCV NS3 protease inhibitor project was to design, synthesize and evaluate a novel hydroxycyclopentene bioisostere to the previously used acyl-hydroxyproline moiety. The investigation revealed that it was possible to synthesize inhibitors containing this new bioisostere that were potent in the low nanomolar range. Further optimization by rigidification of the most active inhibitor resulted in equipotent macrocyclic compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 108
Keyword
Alzheimer's disease, BACE-1, transition state mimetic, tertiary hydroxyl group, hydroxyethylene, statine, hydroxyethylamine, hepatitis C, HCV NS3, bioisostere, protease inhibitor.
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-108985 (URN)978-91-554-7623-6 (ISBN)
Public defence
2009-11-20, B42, Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-10-29 Created: 2009-10-06 Last updated: 2011-03-02Bibliographically approved
2. Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands
Open this publication in new window or tab >>Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene.

In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 183
Keyword
Palladium, Carbonylation, Positron emission tomography, PET, Carbon-11, Fluor-18, Radiochemistry, Amyloidosis, Palladium, Karbonyleringar, Positronemissionstomografi, PET, Kol-11, Fluor-18, Radiokemi, Amyloidos
National Category
Pharmaceutical Chemistry Medicinal Chemistry
Research subject
Pharmaceutical Science; Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-213863 (URN)978-91-554-8843-7 (ISBN)
Public defence
2014-02-21, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-01-30 Created: 2014-01-05 Last updated: 2014-02-10

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Nordeman, PatrikSävmarker, JonasEmanuelsson, RikardLarhed, Mats

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