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Design and synthesis of BACE-1 inhibitors utilizing a tertiary hydroxyl motif as the transition state mimic
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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2009 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, no 16, 4711-4714 p.Article in journal (Refereed) Published
Abstract [en]

Two series of drug-like BACE-1 inhibitors with a shielded tertiary   hydroxyl as transition state isostere have been synthesized. The most   potent inhibitor exhibited a BACE-1 IC50 value of 0.23 mu M.

Place, publisher, year, edition, pages
Elsevier , 2009. Vol. 19, no 16, 4711-4714 p.
Keyword [en]
Alzheimer's disease, BACE-1, Enzyme inhibitor, Transition state mimetic
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-109025DOI: 10.1016/j.bmcl.2009.06.065ISI: 000268358800039OAI: oai:DiVA.org:uu-109025DiVA: diva2:242287
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

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Sävmarker, JonasLarhed, Mats

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