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  • 1.
    Andersson, H.O.
    et al.
    Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Fridborg, K.
    Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Lowgren, S.
    Löwgren, S., Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Alterman, M.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Muhlman, A.
    Mühlman, A., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Bjorsne, M.
    Björsne, M., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Garg, N.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Schaal, W.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Classon, B.
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Karlen, A.
    Karlén, A., Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Danielsson, U.H.
    Department of Biochemistry, Uppsala University, Uppsala, Sweden.
    Ahlsen, G.
    Ahlsén, G., Department of Biochemistry, Uppsala University, Uppsala, Sweden.
    Nillroth, U.
    Department of Biochemistry, Uppsala University, Uppsala, Sweden.
    Vrang, L.
    Medivir AB, Lunastigen 7, Huddinge, Sweden.
    Oberg, B.
    Öberg, B., Medivir AB, Lunastigen 7, Huddinge, Sweden.
    Samuelsson, B.
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Unge, T.
    Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden, Inst. of Cell and Molecular Biology, Box 590, Uppsala University, SE-751 24 Uppsala, Sweden.
    Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors2003In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 8, p. 1746-1758Article in journal (Refereed)
    Abstract [en]

    HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.

  • 2.
    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.

  • 3.
    Bäck, Marcus
    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.
    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.
    Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 SubstituentsManuscript (Other academic)
    Abstract [en]

    BACE-1 inhibitors with a hydroxyetylene central core, comprising a methoxy residue in the P1´ position, are presented. Extended P1 substituents were introduced with the aim to explore possible interactions with the S1-S3 pocket. Incorporation of the more advanced P1 substituents produced promising inhibitors in the low micromolar range.

  • 4.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Nyhlén, Jonas
    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.
    Appelgren, Sara
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Borkakoti, Neera
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Jansson, Katarina
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Lindberg, Jimmy
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Nyström, Susanne
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, Anders
    Department of Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, S-751 23 Uppsala, Sweden.
    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-10691 Stockholm, Sweden.
    Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.2008In: Bioorganic & medicinal chemistry, ISSN 1464-3391, Vol. 16, no 21, p. 9471-9486Article in journal (Refereed)
    Abstract [en]

    Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

  • 5.
    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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    Johansson, Per-Ola
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Chen, Yantao
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Belfrage, Anna Karin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Blackman, Michael J.
    Division of Parasitology, National Institute for Medical Research, London, United Kingdom.
    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, Uppsala, Sweden.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden and Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II: use of solid-phase synthesis to explore novel statine motifs2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 13, p. 3353-3366Article in journal (Refereed)
    Abstract [en]

    Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays Ki values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 μM. Several inhibitors have been identified that exhibit Ki values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.

  • 11.
    Johansson, Per-Ola
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Chen, Yantao
    Belfrage, Anna Karin
    Blackman, Michael J.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Jansson, Katarina
    Vrang, Lotta
    Hamelink, Elizabeth
    Hallberg, Anders
    Rosenqvist, Åsa
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Samuelsson, Bertil
    Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, p. 3353-3366Article in journal (Refereed)
    Abstract [en]

      

  • 12.
    Johansson, Per-Ola
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lindberg, Jimmy
    Department of Cell and Molecular Biology, BMC, Uppsala University, Uppsala, Sweden.
    Blackman, Michael J.
    Division of Parasitology, National Institute for Medical Research, United Kingdom.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, 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, Uppsala University, Uppsala, Sweden.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden and Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Design and synthesis of potent inhibitors of plasmepsin I and II: x-ray crystal structure of inhibitor in complex with plasmepsin II2005In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, no 13, p. 4400-4409Article in journal (Refereed)
    Abstract [en]

    New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.

  • 13.
    Lindberg, J.
    et al.
    Dept. of Cell and Molecular Biology, BMC, Uppsala University, SE-751 24, Uppsala, Sweden.
    Pyring, D.
    Lowgren, S.
    Löwgren, S., Dept. of Cell and Molecular Biology, BMC, Uppsala University, SE-751 24, Uppsala, Sweden.
    Rosenquist, A.
    Zuccarello, G.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Zhang, H.
    Medivir AB, Huddinge, Sweden.
    Vrang, L.
    Medivir AB, Huddinge, Sweden.
    Classon, B.
    Medivir AB, Huddinge, Sweden, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceut. Chem., Uppsala University, BMC, Uppsala, Sweden.
    Samuelsson, B.
    Medivir AB, Huddinge, Sweden, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Sweden.
    Unge, T.
    Dept. of Cell and Molecular Biology, BMC, Uppsala University, SE-751 24, Uppsala, Sweden.
    Symmetric fluoro-substituted diol-based HIV protease inhibitors: Ortho-fluorinated and meta-fluorinated P1/P1'-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy2004In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 271, no 22, p. 4594-4602Article in journal (Refereed)
    Abstract [en]

    HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 Å resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono- and difluoro-substituted benzyloxy side groups in P1/P1' and indanoleamine side groups in P2/P2'. The ortho- and meta-fluorinated P1/P1'-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluorosubstitutions are well accommodated in the protease S1/S1' subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.

  • 14.
    Nilsson, Jonas W.
    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
    AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
    Nilsson, Ingemar
    AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
    Samuelsson, Bertil
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden and Medivir AB, Huddinge, Sweden.
    Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex2001In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 19, p. 3985-4001Article in journal (Refereed)
    Abstract [en]

    A 4-amino-2-carboxymethyl-3-morpholinone structural motif derived from malic acid has been used to mimic d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. The arginine in d-Phe-Pro-Arg was replaced by the more rigid P1 truncated p-amidinobenzylamine (Pab). These new thrombin inhibitors were used to probe the inhibitor binding site of α-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 μM. Interestingly, the stereochemistry of the 4-amino-2-carboxymethyl-3-morpholinone motif is reversed for the most active compounds compared to that of a previously reported 2-carboxymethyl-3-morpholinone series. The X-ray crystal structure of the lead inhibitor cocrystallized with α-thrombin is discussed.

  • 15.
    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%.

  • 16.
    Noteberg, D
    et al.
    AstraZeneca, Dept Med Chem, S-43183 Molndal, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Stockholm Univ, Dept Organ Chem, S-10691 Stockholm, Sweden.
    Branalt, J
    AstraZeneca, Dept Med Chem, S-43183 Molndal, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Stockholm Univ, Dept Organ Chem, S-10691 Stockholm, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Linschoten, M
    AstraZeneca, Dept Med Chem, S-43183 Molndal, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Stockholm Univ, Dept Organ Chem, S-10691 Stockholm, Sweden.
    Musil, D
    AstraZeneca, Dept Med Chem, S-43183 Molndal, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Stockholm Univ, Dept Organ Chem, S-10691 Stockholm, Sweden.
    Nystrom, JE
    Zuccarello, G
    AstraZeneca, Dept Med Chem, S-43183 Molndal, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Stockholm Univ, Dept Organ Chem, S-10691 Stockholm, Sweden.
    Samuelsson, B
    New proline mimetics: Synthesis of thrombin inhibitors incorporating cyclopentane- and cyclopentenedicarboxylic acid templates in the P2 position. Binding conformation investigated by X-ray crystallography2000In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 43, no 9, p. 1705-1713Article in journal (Refereed)
    Abstract [en]

    With the aim to prepare nonpeptidic thrombin inhibitors, the amino acids of the thrombin-inhibiting tripeptide chain D-Phe-Pro-Arg were replaced with isosteres. Arg was replaced with the more rigid P1 truncated p-amidinobenzylamine (Pab), Pro with either cyclopentane-1,2-dicarboxylic acid or cyclopentene-1,5-dicarboxylic acid, and D-Phe with a series of readily available lipophilic amines. One of the most potent compounds (25, pIC(50) = 6.01) in these series was cocrystallized with thrombin where the X-ray crystal structure provide insight to the structure-activity relationship (SAR).

  • 17. Nötberg, Daniel
    et al.
    Brånalt, Jonas
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Linschoten, Marcel
    Musil, Djordje
    Nyström, Jan-Erik
    Zuccarello, Guido
    Samuelsson, Bertil
    New Proline Mimetics: Synthesis of Thrombin Inhibitors Incorporating2000In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 43, p. 1705-1713Article in journal (Refereed)
    Abstract [en]

      

  • 18.
    Oscarsson, K
    et al.
    Stockholm Univ, Arrhenius Lab, Dept Organ Chem, SE-10691 Stockholm, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Univ Uppsala, BMC, Dept Organ Pharmaceut Chem, S-75123 Uppsala, Sweden Medivir AB, SE-14144 Huddinge, Sweden.
    Classon, B
    Stockholm Univ, Arrhenius Lab, Dept Organ Chem, SE-10691 Stockholm, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden Univ Uppsala, BMC, Dept Organ Pharmaceut Chem, S-75123 Uppsala, Sweden Medivir AB, SE-14144 Huddinge, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Hallberg, A
    Samuelsson, B
    Solid phase assisted synthesis of HIV-1 protease inhibitors. Expedient entry to unsymmetrical substitution of a C-2 symmetric template2000In: Canadian journal of chemistry (Print), ISSN 0008-4042, E-ISSN 1480-3291, Vol. 78, no 6, p. 829-837Article in journal (Refereed)
    Abstract [en]

    A solid phase synthesis has been developed leading up to unsymmetrical HIV-1 protease inhibitors that are not readily available by conventional solution phase chemistry (18a-g). To prepare these compounds the hydroxyl group of (1S,2R)-(-)-cis-1-phthalimido-2-indanol (3) was coupled to a Merrifield resin via a dihydropyrane linker. Cleavage of the phthalimido protecting group and reaction of the liberated amine with the bis-activated symmetrical diacid 15 resulted in the resin bound amide 16. Coupling of 16 with amino acids and amines followed by hydrolysis produced the desired unsymmetrical products 18a-g from which potent HIV-1 protease inhibitors were identified, e.g., 18e (k(i) = 0.1 nM), 18a (k(i) = 0.2 nM) and 18c (k(i) = 2 nM).

  • 19. Pyring, David
    et al.
    Lindberg, Jimmy
    Rosenquist, Åsa
    Zuccarello, Guido
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry.
    Zhang, Hong
    Vrang, Lotta
    Unge, Torsten
    Classon, Björn
    Hallberg, Anders
    Samuelsson, Bertil
    Design and Synthesis of Potent C2-Symmetric Diol-Based HIV-1 Protease2001In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 44, p. 3083-3091Article in journal (Refereed)
    Abstract [en]

      

  • 20.
    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.

  • 21.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Belda, Oscar
    Medivir AB, Lunastigen 7, SE-141 44 Huddinge, Sweden.
    Johansson, Per-Ola
    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.
    Dahlgren, Anders
    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.
    Design and synthesis of novel macrocyclic BACE-1 inhibitorsManuscript (preprint) (Other academic)
    Abstract [en]

    A series of arylketo-containing P1-P3 linked macrocyclic inhibitors was designed and synthesized and compared with a previously known and extensively used corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme and cell-based potencies. Several inhibitors displayed a substantial increase in Caco-2 cell-based permeability and notably also with retained potencies, showing that this approach might lead to centrally active BACE-1 inhibitors.

  • 22.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Belda, Oscar
    Medivir AB, Huddinge, Sweden.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Lindberg, Jimmy
    Medivir AB, Huddinge, Sweden.
    Samuelsson, Bertil
    Medivir AB, Huddinge, Sweden.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Design and Synthesis of Novel Arylketo-containing P1-P3 Linked Macro-cyclic BACE-1 Inhibitors2015In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 9, p. 13-26Article in journal (Refereed)
    Abstract [en]

    A series of arylketo-containing P1-P3 linked macrocyclic BACE-1 inhibitors were designed, synthesized, and compared with compounds with a previously known and extensively studied corresponding P2 isophthalamide moiety with the aim to improve on permeability whilst retaining the enzyme- and cell-based activities. Several inhibitors displayed substantial increases in Caco-2 cell-based permeability compared to earlier synthesized inhibitors and notably also with retained activities, showing that this approach might yield BACE-1 inhibitors with improved properties.

  • 23.
    Sandgren, Veronica
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    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.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Design and synthesis of hydroxyethylene-based BACE-1 inhibitors incorporating extended P1 substituents2013In: Open Medicinal Chemistry Journal, ISSN 1874-1045, Vol. 7, p. 1-15Article in journal (Refereed)
    Abstract [en]

    Novel BACE-1 inhibitors with a hydroxyethylene central core have been  developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e., 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.

  • 24.
    Sandgren, Veronica
    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.
    Dahlgren, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Exploration of the active site of BACE-1: Design and synthesis of inhibitors incorporating substituted cyclopentanes in the P2 positionManuscript (preprint) (Other academic)
    Abstract [en]

    A novel hydroxyethylene (HE) core structure with an O-methyl group in the P1´ position, previously reported by our group, has been further evaluated by introducing a substituted cyclopentane moiety in the P2 position. Results from earlier published work suggest that inhibitors containing the novel O-methyl HE core may result in inhibitors displaying promising potency against BACE-1 as well as selectivity towards cathepsin D. Furthermore, there is a general need for new and improved moieties in the P2 position for many BACE-1 inhibitors, e.g., the widely used substituted P2 isophthalamide structure often gives rise to inhibitors suffering from poor pharmacokinetics, including insufficient blood-brain barrier permeability. Different stereoisomers of the P2 cyclopentane moieties and a selection of P3 substituents have been examined. In addition, a macrocyclization study linking the P1 and P3 moieties was performed and biological results are discussed.

  • 25.
    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.

  • 26.
    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.

  • 27.
    Wachtmeister, J.
    et al.
    Department of Organic Chemistry, Arrhenius Lab., Stockholm Univ., S., Stockholm, Sweden.
    Muhlman, A.
    Mühlman, A., Department of Organic Chemistry, Arrhenius Lab., Stockholm Univ., S., Stockholm, Sweden.
    Classon, B.
    Department of Organic Chemistry, Arrhenius Lab., Stockholm Univ., S., Stockholm, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, BMC, SE-751 23, Uppsala, Sweden.
    Samuelsson, B.
    Department of Organic Chemistry, Arrhenius Lab., Stockholm Univ., S., Stockholm, Sweden.
    Impact of the central hydroxyl groups on the activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid2000In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 56, no 20, p. 3219-3225Article in journal (Refereed)
    Abstract [en]

    The influence of the central hydroxyl groups on the anti-viral activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid has been examined. L-Iditol was synthesized and used as a chiral precursor for the synthesis of the corresponding inhibitor with inverted configuration at C-3 and C-4. Key intermediates were 3,4-O-isopropylidene-L-iditol and the activated L-idaric acid succinimidyI ester. The configurations of the central hydroxyl groups required for optimal inhibition of the HIV-1 protease were determined to be the C-3R and C-4R, i.e. the L-manno-configuration. Three C2-symmetric inhibitors were converted to their thiocarbonates and reduced to provide the corresponding hydroxyethyl transition-state mimics. Deletion of the C-4 hydroxyl group in these inhibitors gave no further improvement in the anti-viral activity. (C) 2000 Published by Elsevier Science Ltd.

  • 28.
    Wångsell, Fredrik
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Gustafsson, Karin
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Borkakoti, Neera
    Medivir AB.
    Edlund, Michael
    Medivir AB.
    Jansson, Katarina
    Medivir AB.
    Lindberg, Jimmy
    Medivir AB.
    Hallberg, Anders
    Uppsala University.
    Rosenquist, Åsa
    Medivir AB.
    Samuelsson, Bertil
    Medivir AB.
    Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core2010In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ISSN 0223-5234, Vol. 45, no 3, p. 870-882Article in journal (Refereed)
    Abstract [en]

    We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxyl ethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the PI-position. The final inhibitors were optimized using three different amines to provide the residues in the P2-P3 position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-I assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 Value of 3.1 nM.

1 - 28 of 28
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