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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.
    Dahlgren, Anders
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Branalt, J.
    Brånalt, J., AstraZeneca RandD, Medicinal Chemistry, S-431 83 Mölndal, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Nilsson, I.
    AstraZeneca RandD, Medicinal Chemistry, S-431 83 Mölndal, Sweden.
    Musil, D.
    AstraZeneca RandD, Structural Chemistry Laboratory, S-481 83 Mölndal, Sweden.
    Samuelsson, B.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden, Tel.: +46-8-608-3104.
    Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics2002In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 5, p. 1567-1580Article in journal (Refereed)
    Abstract [en]

    With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC50~5.9 µM. © 2002 Elsevier Science Ltd. All rights reserved.

  • 3.
    Dahlgren, Anders
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Johansson, Per-Ola
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Musil, Djordje
    AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
    Nilsson, Ingemar
    AstraZeneca R&D, Medicinal Chemistry, Mölndal, Sweden.
    Samuelsson, Bertil
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden and Medivir AB, Huddinge, Sweden.
    Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex2002In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 6, p. 1829-1839Article in journal (Refereed)
    Abstract [en]

    A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.

  • 4.
    Dahlgren, Anders
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Vrang, L.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hamelink, E.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., BMC, Uppsala University, S-751 24 Uppsala, Sweden.
    Rosenquist, A.
    Samuelsson, B.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    New inhibitors of the malaria aspartyl proteases plasmepsin I and II2003In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 16, p. 3423-3437Article in journal (Refereed)
    Abstract [en]

    New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.

  • 5.
    Dahlgren, Anders
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Vrang, L.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hamelink, E.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Box 596, S-751 24 Uppsala, Sweden.
    Rosenquist, A.
    Samuelsson, B.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II2003In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 6, p. 827-841Article in journal (Refereed)
    Abstract [en]

    With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.

  • 6.
    Johansson, Per-Ola
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Jansson, Katarina
    Medivir AB, Huddinge, Sweden.
    Vrang, Lotta
    Medivir AB, Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Huddinge, Sweden.
    Hallberg, Anders
    Department of Medicinal Chemistry, Uppsala University, BMC, Uppsala, Sweden.
    Rosenqvist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template2006In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, p. 5136-5151Article in journal (Refereed)
    Abstract [en]

    The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

  • 7.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Agback, Tatiana
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Johansson, Per-Ola
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Lindberg, Jimmy
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Belda, Oscar
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes2012In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 29, no 14, p. 4377-4389Article in journal (Refereed)
    Abstract [en]

    A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzyme-inhibitor interactions are discussed.

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