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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
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Medivir AB, Huddinge, Sweden.
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2007 (English)In: Bioorganic & medicinal chemistry, ISSN 0968-0896, 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]
HCV; NS3; Protease inhibitor; N-Acyl-l-hydroxyproline mimic; 4-Hydroxy-cyclopent-2-ene-1, 2-dicarboxylic acid; Cyclopentene
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13983DOI: 10.1016/j.bmc.2006.10.044OAI: oai:DiVA.org:liu-13983DiVA: diva2:22383
Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2009-05-15
In thesis
1. Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
Open this publication in new window or tab >>Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Structure-based drug design and combinatorial chemistry play important roles in the search for new drugs, and both these elements of medicinal chemistry were included in the present studies. This thesis outlines the synthesis of protease inhibitors against thrombin and the HCV NS3 protease, as well as the synthesis of a combinatorial library using solid phase chemistry.In the current work potent thrombin inhibitors were generated based on the D-Phe-Pro-Arg motif incorporating cyclopentene and cyclohexene scaffolds that were synthesized by ring-closing metathesis chemistry. A structure-activity relationship study was carried out using the crystallographic results for one of the inhibitors co-crystallized with thrombin. HCV NS3 protease inhibitors comprising the proline bioisostere 4-hydroxy-cyclopent-2-ene-1,2-dicarbboxylic acid were synthesized displaying low nanomolar activity. The stereochemistry and regiochemistry of the scaffolds were determined by NOESY and HMBC spectra, respectively. The final diastereomeric target compounds were isolated and annotated by applying TOCSY and ROESY NMR experiments. Furthermore, a 4-phenyl-2-carboxypiperazine targeted combinatorial chemistry library was synthesized to be used early in the lead discovery phase. This was done using a scaffold that was synthesized by palladiumcatalyzed aromatic amination chemistry and subsequently derivatized with eight electrophiles and ten nucleophiles.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi, 2005
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 990
Series
Keyword
organic chemistry, organic synthesis, combinatorial synthesis, metathesis, olefin metathesis, thrombin, HCV, NS3, protease, proline isosteres, inhibitor
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-4938 (URN)91-85457-78-7 (ISBN)
Public defence
2005-12-09, Sal Planck, Fysikhuset, Campus Vall, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2009-06-05
2. Design and Synthesis of Serine and Aspartic Protease Inhibitors
Open this publication in new window or tab >>Design and Synthesis of Serine and Aspartic Protease Inhibitors
2006 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the design and synthesis of compounds that are

intended to inhibit serine and aspartic proteases. The first part of the text deals with preparation of inhibitors of the hepatitis C virus (HCV) NS3 serine protease. Hepatitis C is predominantly a chronic disease that afflicts about 170 million people worldwide. The NS3 protease, encoded by HCV, is essential for replication of the virus and has become one of the main targets when developing drugs to fight HCV. The inhibitors discussed here constitute surrogates for the widely used N-acyl-hydroxyproline isostere designated 4-hydroxy-cyclopentene. The stereochemistry of the 4-hydroxy-cyclopentene scaffold was determined by nuclear overhauser effect spectroscopy (NOESY) and the regiochemistry by heteronuclear multiple bond correlation (HMBC). The scaffold was decorated with different substituents to obtain both linear and macrocyclic HCV NS3 protease inhibitors that display low nanomolar activity. The second part of the thesis describes the design and synthesis of potential aspartic protease inhibitors. The hydroxyethylene motif was used as a noncleavable transition state isostere. The synthetic route yielded a pivotal intermediate with excellent stereochemical control, which was corroborated by NOESY experiments. This intermediate can be diversified with different substituents to furnish novel aspartic protease inhibitors.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi, 2006. 51 p.
Series
Linköping Studies in Science and Technology. Thesis, ISSN 0280-7971 ; 1264
Series
Keyword
organic chemistry, organic synthesis, metathesis, HCV, NS3, protease, proline isosteres, inhibitor, aspartic protease inhibitors, hydroxyethylene
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-7372 (URN)91–85523–21–6 (ISBN)
Presentation
2006-09-29, Schrödinger (E324), Hus E, Campus Valla, Linköpings universitet, Linköping, 14:00 (English)
Opponent
Supervisors
Note
Report code: LIU-TEK-LIC-2006:45Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2009-06-09

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Thorstensson, FredrikWångsell, FredrikKvarnström, Ingemar

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