liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
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.
Department of Medicinal Chemistry, AstraZeneca, Mölndal, Sweden.
Department of Medicinal Chemistry, AstraZeneca, Mölndal, Sweden.
Show others and affiliations
2003 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 7, 1165-1179 p.Article in journal (Refereed) Published
Abstract [en]

The thrombin inhibitory tripeptide d-Phe-Pro-Arg has been mimicked using either cyclopentenedicarboxylic derivatives or a cyclohexenedicarboxylic derivative as surrogate for the P2 proline. In the P3 position, tertiary amides were optimized as d-Phe P3 replacements. The P1 arginine was, in all compounds, substituted with the more rigid and biocompatible 4-aminomethylbenzamidine. One of the novel inhibitors was cocrystallized with α-thrombin and subjected to X-ray analysis. From analysis of the X-ray crystal structure, new ligands were designed leading to significantly improved binding affinity, the lead candidate exhibiting an in vitro IC50 of 49 nM.

Place, publisher, year, edition, pages
2003. Vol. 46, no 7, 1165-1179 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13468DOI: 10.1021/jm021065aOAI: oai:DiVA.org:liu-13468DiVA: diva2:20822
Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2009-06-05
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

Open Access in DiVA

No full text

Other links

Publisher's full textLink to Ph.D. Thesis

Authority records BETA

Thorstensson, FredrikKvarnström, Ingemar

Search in DiVA

By author/editor
Thorstensson, FredrikKvarnström, Ingemar
By organisation
Organic Chemistry The Institute of Technology
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 69 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf