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Synthesis of novel potent hepatitis C virus NS3 protease inhibitors: discovery of 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a N-acyl-L-hydroxyproline bioisostere
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2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 2, 827-838 p.Article in journal (Refereed) Published
Abstract [en]

Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a Ki value of 1.1 nM.

Place, publisher, year, edition, pages
2007. Vol. 15, no 2, 827-838 p.
Keyword [en]
Cyclopentanes/*chemical synthesis/*pharmacology, Dicarboxylic Acids/*chemical synthesis/*pharmacology, Indicators and Reagents, Kinetics, Magnetic Resonance Spectroscopy, Models; Molecular, Protease Inhibitors/*chemical synthesis/*pharmacology, Stereoisomerism, Structure-Activity Relationship, Viral Nonstructural Proteins/*antagonists & inhibitors
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-17096DOI: 10.1016/j.bmc.2006.10.044ISI: 000243315300021PubMedID: 17107807OAI: oai:DiVA.org:uu-17096DiVA: diva2:44867
Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2012-08-03Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 108
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
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)
Available from: 2009-10-29 Created: 2009-10-06 Last updated: 2011-03-02Bibliographically approved

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