Steven Swallow

Publications (7)22.75 Total impact

• Article: Non-nucleoside inhibitors of HCV NS5B polymerase. Part 1: Synthetic and computational exploration of the binding modes of benzothiadiazine and 1,4-benzothiazine HCV NS5b polymerase inhibitors.

  Robert T Hendricks, Jay B Fell, James F Blake, John P Fischer, John E Robinson, Stacey R Spencer, Peter J Stengel, April L Bernacki, Vincent J P Leveque, Sophie Le Pogam, Sonal Rajyaguru, Isabel Najera, John A Josey, Jason R Harris, Steven Swallow
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  ABSTRACT: The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.
  Bioorganic & medicinal chemistry letters 06/2009; 19(13):3637-41. · 2.65 Impact Factor
• Source

  Available from: Christian Sund

  Article: The design, synthesis, and antiviral activity of monofluoro and difluoro analogues of 4'-azidocytidine against hepatitis C virus replication: the discovery of 4'-azido-2'-deoxy-2'-fluorocytidine and 4'-azido-2'-dideoxy-2',2'-difluorocytidine.

  David B Smith, Genadiy Kalayanov, Christian Sund, Anna Winqvist, Tatiana Maltseva, Vincent J-P Leveque, Sonal Rajyaguru, Sophie Le Pogam, Isabel Najera, Kurt Benkestock, Xiao-Xiong Zhou, Ann C Kaiser, Hans Maag, Nick Cammack, Joseph A Martin, Steven Swallow, Nils Gunnar Johansson, Klaus Klumpp, Mark Smith
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  ABSTRACT: The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem. 2006, 281, 3793; Bioorg. Med. Chem. Lett. 2007, 17, 2570) as a potent inhibitor of RNA synthesis by NS5B (EC(50) = 1.28 microM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4'-azidocytidine. The most potent compounds in this series were 4'-azido-2'-deoxy-2',2'-difluorocytidine and 4'-azido-2'-deoxy-2'-fluoroarabinocytidine with antiviral EC(50) of 66 nM and 24 nM in the HCV replicon system, respectively. The structure-activity relationships within this series were discussed, which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4'-azidocytidine (3).
  Journal of Medicinal Chemistry 05/2009; 52(9):2971-8. · 4.80 Impact Factor
• Source

  Available from: Christian Sund

  Article: The design, synthesis, and antiviral activity of 4'-azidocytidine analogues against hepatitis C virus replication: the discovery of 4'-azidoarabinocytidine.

  David B Smith, Genadiy Kalayanov, Christian Sund, Anna Winqvist, Pedro Pinho, Tatiana Maltseva, Veronique Morisson, Vincent Leveque, Sonal Rajyaguru, Sophie Le Pogam, Isabel Najera, Kurt Benkestock, Xiao-Xiong Zhou, Hans Maag, Nick Cammack, Joseph A Martin, Steven Swallow, Nils Gunnar Johansson, Klaus Klumpp, Mark Smith
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  ABSTRACT: 4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.
  Journal of Medicinal Chemistry 01/2009; 52(1):219-23. · 4.80 Impact Factor
• Article: 3-Hydroxyisoquinolines as inhibitors of HCV NS5b RNA-dependent RNA polymerase.

  Robert T Hendricks, Stacey R Spencer, James F Blake, Jay B Fell, John P Fischer, Peter J Stengel, Vincent J P Leveque, Sophie Lepogam, Sonal Rajyaguru, Isabel Najera, John A Josey, Steven Swallow
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  ABSTRACT: Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure-activity relationships are detailed, along with enzyme and cellular activity.
  Bioorganic & medicinal chemistry letters 12/2008; 19(2):410-4. · 2.65 Impact Factor
• Article: Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase.

  Zachary K Sweeney, James P Dunn, Yu Li, Gabrielle Heilek, Pete Dunten, Todd R Elworthy, Xiaochun Han, Seth F Harris, Donald R Hirschfeld, J Heather Hogg, [......], Taraneh Mirzadegan, Michael G Roepel, Y David Saito, Tania M P C Silva, Steven Swallow, Jahari L Tracy, Armando Villasenor, Harit Vora, Amy S Zhou, Klaus Klumpp
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  ABSTRACT: A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
  Bioorganic & medicinal chemistry letters 08/2008; 18(15):4352-4. · 2.65 Impact Factor
• Article: Discovery of triazolinone non-nucleoside inhibitors of HIV reverse transcriptase.

  Zachary K Sweeney, Sahaja Acharya, Andrew Briggs, James P Dunn, Todd R Elworthy, Jennifer Fretland, Anthony M Giannetti, Gabrielle Heilek, Yu Li, Ann C Kaiser, Michael Martin, Y David Saito, Mark Smith, Judy M Suh, Steven Swallow, Jeffrey Wu, Julie Q Hang, Amy S Zhou, Klaus Klumpp
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  ABSTRACT: Novel non-nucleoside inhibitors of HIV-RT that contain pyridazinone isosteres were prepared, and a series of triazolinones were found to be potent inhibitors of HIV replication. These compounds were active against several NNRTI-resistant virus strains. Pharmacokinetic studies indicated that inhibitor 7e has good bioavailability in rats. Several fragments of inhibitor 7c were prepared, and the binding of these compounds to HIV-RT was analyzed by surface plasmon resonance spectroscopy.
  Bioorganic & medicinal chemistry letters 07/2008; 18(15):4348-51. · 2.65 Impact Factor
• Article: Design, synthesis, and antiviral properties of 4'-substituted ribonucleosides as inhibitors of hepatitis C virus replication: the discovery of R1479.

  David B Smith, Joseph A Martin, Klaus Klumpp, Stewart J Baker, Peter A Blomgren, Rene Devos, Caroline Granycome, Julie Hang, Christopher J Hobbs, Wen-Rong Jiang, [......], Graham Maile, John H Merrett, Arkadius Pichota, Keshab Sarma, Mark Smith, Steven Swallow, Julian Symons, David Vesey, Isabel Najera, Nick Cammack
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  ABSTRACT: A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.
  Bioorganic & Medicinal Chemistry Letters 06/2007; 17(9):2570-6. · 2.55 Impact Factor