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  • 1.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Johansson, Per-Ola
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Wångsell, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Thorstensson, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Ayesa, Susana
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Wähling, Horst
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Pelcman, Mikael
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Jansson, Katarina
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Lindström, Stefan
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Wallberg, Hans
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Classon, Björn
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Rydergård, Christina
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Vrang, Lotta
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, Anders
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden/Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.2007In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 7184-7202Article in journal (Refereed)
    Abstract [en]

    Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

  • 2.
    Nilsson, Jonas W.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thorstensson, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Oprea, Tudor
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Samuelsson, Bertil
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Nilsson, Ingemar
    Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold2001In: Journal of Combinatorial Chemistry, ISSN 2156-8952, Vol. 3, no 6, p. 546-553Article in journal (Refereed)
    Abstract [en]

    Strategies for finding novel structures of therapeutical interest are discussed. The rationale for the selection of the two scaffolds N4-(m-aminophenyl)-piperazine-2-carboxylic acid E and N4-(o-aminophenyl)-piperazine-2-carboxylic F is described. The synthesis of the appropriate precursors to scaffold E and F and their use in solid-phase chemistry are described. A 160-member library was produced combining these novel piperazine scaffolds with eight sulfonyl chlorides/acid chlorides and 10 amines. The compound library prepared was analyzed using LC-MS, showing the expected base peak in all wells at an average purity of 82%.

  • 3.
    Thorstensson, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Structure-Based Design and Synthesis of Protease Inhibitors Using Cycloalkenes as Proline Bioisosteres and Combinatorial Syntheses of a Targeted Library2005Doctoral 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.

    List of papers
    1. Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
    Open this publication in new window or tab >>Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
    Show others...
    2001 (English)In: Journal of Combinatorial Chemistry, ISSN 2156-8952, Vol. 3, no 6, p. 546-553Article in journal (Refereed) Published
    Abstract [en]

    Strategies for finding novel structures of therapeutical interest are discussed. The rationale for the selection of the two scaffolds N4-(m-aminophenyl)-piperazine-2-carboxylic acid E and N4-(o-aminophenyl)-piperazine-2-carboxylic F is described. The synthesis of the appropriate precursors to scaffold E and F and their use in solid-phase chemistry are described. A 160-member library was produced combining these novel piperazine scaffolds with eight sulfonyl chlorides/acid chlorides and 10 amines. The compound library prepared was analyzed using LC-MS, showing the expected base peak in all wells at an average purity of 82%.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2001
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13467 (URN)10.1021/cc010013o (DOI)
    Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2018-05-21
    2. Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
    Open this publication in new window or tab >>Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives
    Show others...
    2003 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 7, p. 1165-1179Article 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.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13468 (URN)10.1021/jm021065a (DOI)
    Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2009-06-05
    3. 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
    Open this publication in new window or tab >>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
    Show others...
    2007 (English)In: Bioorganic & medicinal chemistry, ISSN 0968-0896, Vol. 15, no 2, p. 827-838Article 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.

    Keywords
    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:nbn:se:liu:diva-13983 (URN)10.1016/j.bmc.2006.10.044 (DOI)
    Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2009-05-15
  • 4.
    Thorstensson, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Synthesis of a targeted library and thrombin inhibitors using organometallic chemistry2002Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The use of organometallic chemistry in the pursuit of novel scaffolds is outline d. A 4-phenyl- 2-carboxy-piperazine targeted combinatorial chemistry library has been synthesized aimed at the early lead discovery phase. This was done using a scaffold that was synthesized by palladium-catalyzed aromatic amination chemistry and subsequently derivatized with 8 electrophiles and I O nucleophiles. Furthermore, ring-closing metathesis chemistry reactions were employed to synthesize the scaffolds cyclopent-2-ene-l, 2-dicarboxylic acid 1-methyl ester and cyclohex-2-ene-1, 2-dicarboxylic acid 1-methyl ester. These were used as proline isosteres in the synthesis of thrombin inhibitors based on the D-Phe-Pro-Arg motif. The scaffolds were derivatized with para-amidino benzylamine and several secondary anilines. A structure-activity relationship study is also described that was based on crystallographic results for one of the inhibitors co-crystallized with thrombin.

  • 5.
    Thorstensson, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Musil, Djordje
    Department of Medicinal Chemistry, AstraZeneca, Mölndal, Sweden.
    Nilsson, Ingemar
    Department of Medicinal Chemistry, AstraZeneca, Mölndal, Sweden.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden.
    Synthesis of Novel Thrombin Inhibitors. Use of Ring-Closing Metathesis Reactions for Synthesis of P2 Cyclopentene and Cyclohexene Dicarboxylic Acid Derivatives2003In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 7, p. 1165-1179Article in journal (Refereed)
    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.

  • 6.
    Thorstensson, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Wångsell, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Vrang, Lotta
    Medivir AB, Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Huddinge, Sweden.
    Hallberg, Anders
    Department of Medicinal Chemistry, BMC, Uppsala University, Uppsala, Sweden.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    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 Bioisostere2007In: Bioorganic & medicinal chemistry, ISSN 0968-0896, Vol. 15, no 2, p. 827-838Article in journal (Refereed)
    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.

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