ChemMedChem

Cover image for Vol. 8 Issue 4

Special Issue: Obesity, Diabetes and Metabolic Syndrome

April 2013

Volume 8, Issue 4

Pages 533–670

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Cover Picture: 2-Phenoxy-nicotinamides are Potent Agonists at the Bile Acid Receptor GPBAR1 (TGR5) (ChemMedChem 4/2013) (page 533)

      Dr. Rainer E. Martin, Dr. Caterina Bissantz, Olivier Gavelle, Christoph Kuratli, Dr. Henrietta Dehmlow, Dr. Hans G. F. Richter, Dr. Ulrike Obst Sander, Dr. Shawn D. Erickson, Dr. Kyungjin Kim, Dr. Sherrie Lynn Pietranico-Cole, Dr. Rubén Alvarez-Sánchez and Dr. Christoph Ullmer

      Version of Record online: 25 MAR 2013 | DOI: 10.1002/cmdc.201390010

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      The front cover picture shows a 3D homology model of the human G protein-coupled bile acid receptor (GPBAR1; carbon atoms in green). The full receptor structure is shown (top right) with the proposed binding site of GPBAR1 agonists indicated (red ellipse). The main picture shows a zoom of this binding site into which taurolithocholic acid (TLCA; carbon atoms in cyan) and a 2-phenoxy-nicotinamide agonist (carbon atoms in magenta) are docked. The alignment of TLCA with our advanced lead compounds enabled the identification of the optimal attachment point for a polar vector, which was critical to improve the physicochemical properties of the series. For more details, see the Communication by Rainer E. Martin et al. on p. 569 ff.

    2. You have free access to this content
      Inside Cover: Effect of C7 Modifications on Benzothiadiazine-1,1-dioxide Derivatives on Their Inhibitory Activity and Selectivity toward Aldose Reductase (ChemMedChem 4/2013) (page 534)

      Shuzhen Zhang, Xin Chen, Shagufta Parveen, Saghir Hussain, Yanchun Yang, Chaojun Jing and Prof. Dr. Changjin Zhu

      Version of Record online: 25 MAR 2013 | DOI: 10.1002/cmdc.201390011

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      The inside cover picture shows a benzothiadiazine-1,1-dioxide inhibitor of aldose reductase (ALR2) bound in the active site. Structure–activity relationship studies led to inhibitors with enhanced activity and selectivity, highlighting the important role of the C7 side chain and providing insight into the pharmacophore requirements for ALR2 inhibition. For more details, see the Full Paper by Changjin Zhu et al. on p. 603 ff.

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      Back Cover: Synthesis, Characterization and Pharmacodynamics of Vitamin-B12-Conjugated Glucagon-Like Peptide-1 (ChemMedChem 4/2013) (page 800)

      Dr. Susan Clardy-James, Dr. Oleg G. Chepurny, Dr. Colin A. Leech, Prof. George G. Holz and Prof. Robert P. Doyle

      Version of Record online: 25 MAR 2013 | DOI: 10.1002/cmdc.201390014

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      The back cover picture shows two views at 150° rotation of vitamin B12 conjugated to the potent anti-hyperglycemia peptide glucagon-like peptide-1 (GLP-1). The conjugate displays similar receptor binding and agonism to unconjugated GLP-1, including insulin potentiation from human transplant pancreatic islet cells, which bodes well for oral delivery of GLP-1 through the B12 dietary pathway. For more details, see the Communication by Robert P. Doyle et al. on p. 582 ff.

  2. Editorial

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
  3. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
  4. News

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
  5. Minireviews

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Chemerin and Vaspin: Possible Targets to Treat Obesity? (pages 549–559)

      Stephan Schultz and Prof. Dr. Annette G. Beck-Sickinger

      Version of Record online: 28 DEC 2012 | DOI: 10.1002/cmdc.201200448

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      The skinny on adipokines: Chemerin and vaspin exert several physiological functions within the human body. Both of these adipokines affect metabolically related tissues and ultimately contribute to obesity. As a result, the development of chemerin- and vaspin-derived small molecules has emerged as pharmaceutical strategy to treat obesity.

    2. Structural Aspects of Gut Peptides with Therapeutic Potential for Type 2 Diabetes (pages 560–567)

      Dr. Chandralal M. Hewage and Dr. Kalyana C. Venneti

      Version of Record online: 4 JAN 2013 | DOI: 10.1002/cmdc.201200445

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      Insulin release: This Minireview summaries the structural features of important gut peptides that give rise to their potential as therapeutic agents against type 2 diabetes. The various structural modifications investigated are discussed in the context of improving the properties of these endogenous ligands for use as drugs.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. 2-Phenoxy-nicotinamides are Potent Agonists at the Bile Acid Receptor GPBAR1 (TGR5) (pages 569–576)

      Dr. Rainer E. Martin, Dr. Caterina Bissantz, Olivier Gavelle, Christoph Kuratli, Dr. Henrietta Dehmlow, Dr. Hans G. F. Richter, Dr. Ulrike Obst Sander, Dr. Shawn D. Erickson, Dr. Kyungjin Kim, Dr. Sherrie Lynn Pietranico-Cole, Dr. Rubén Alvarez-Sánchez and Dr. Christoph Ullmer

      Version of Record online: 7 DEC 2012 | DOI: 10.1002/cmdc.201200474

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      Potency with potential: 2-Phenoxy- nicotinamides were identified as potent agonists at the GPBAR1 receptor, a target in the treatment of obesity, type 2 diabetes and metabolic syndrome. Extensive structure–activity relationship studies supported by homology modeling and docking resulted in the identification of optimized GPBAR1 agonists, potent against both human and mouse receptors, endowed with favorable physicochemical properties and good metabolic stability.

    2. Design and Synthesis of (R)-1-Arylsulfonylpiperidine-2-carboxamides as 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors (pages 577–581)

      Dr. Guangxin Xia, Lin Liu, Dr. Haiyan Liu, Dr. Jianxin Yu, Zhenmin Xu, Qian Chen, Chen Ma, Dr. Ping Li, Prof. Bing Xiong, Dr. Xuejun Liu and Prof. Jingkang Shen

      Version of Record online: 7 MAR 2013 | DOI: 10.1002/cmdc.201300022

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      R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.

    3. Synthesis, Characterization and Pharmacodynamics of Vitamin-B12-Conjugated Glucagon-Like Peptide-1 (pages 582–586)

      Dr. Susan Clardy-James, Dr. Oleg G. Chepurny, Dr. Colin A. Leech, Prof. George G. Holz and Prof. Robert P. Doyle

      Version of Record online: 30 NOV 2012 | DOI: 10.1002/cmdc.201200461

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      Clearing the way: Glucagon-like peptide-1 (GLP-1) receptor agonists are proving a potent weapon in the treatment of type II diabetes. A new vitamin B12–GLP-1 conjugate is investigated and shown to have insulinotropic properties similar to the unmodified peptide. These results are critical to the exploitation of the vitamin B12 oral uptake pathway for peptide delivery.

    4. [3H]UR-PLN196: A Selective Nonpeptide Radioligand and Insurmountable Antagonist for the Neuropeptide Y Y2 Receptor (pages 587–593)

      Dr. Nikola Pluym, Paul Baumeister, Dr. Max Keller, Prof. Dr. Günther Bernhardt and Prof. Dr. Armin Buschauer

      Version of Record online: 29 JAN 2013 | DOI: 10.1002/cmdc.201200566

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      Radioing in on NPY: Attachment of a [2,3-3H]propionyl group through an appropriate linker to the guanidine group of an (S)-argininamide-type neuropeptide Y (NPY) Y2 receptor antagonist resulted in a subtype-selective radioligand.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. (Val8)GLP-1-Glu-PAL: a GLP-1 Agonist That Improves Hippocampal Neurogenesis, Glucose Homeostasis, and β-Cell Function in High-Fat-Fed Mice (pages 595–602)

      Rachael Lennox, Dr. David W. Porter, Prof. Peter R. Flatt and Dr. Victor A. Gault

      Version of Record online: 8 NOV 2012 | DOI: 10.1002/cmdc.201200409

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      Hormone with staying power: A novel GLP-1 peptide, (Val8)GLP-1-Glu-PAL, was engineered with Ala8[RIGHTWARDS ARROW]Val8 substitution and additional incorporation of a C16 fatty acid moiety at Lys26 via a glutamic acid linker. (Val8)GLP-1-Glu-PAL is a long-acting GLP-1 peptide that significantly improves hippocampal neurogenesis, glucose homeostasis, and insulin release in mice fed a high-fat diet.

    2. Effect of C7 Modifications on Benzothiadiazine-1,1-dioxide Derivatives on Their Inhibitory Activity and Selectivity toward Aldose Reductase (pages 603–613)

      Shuzhen Zhang, Xin Chen, Shagufta Parveen, Saghir Hussain, Yanchun Yang, Chaojun Jing and Prof. Dr. Changjin Zhu

      Version of Record online: 7 NOV 2012 | DOI: 10.1002/cmdc.201200386

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      Reducing reductase: Modification of the C7 position of benzothiadiazine-1,1-dioxide with hydrophobic or bulky substituents led to a group of new aldose reductase (ALR2) inhibitors. These compounds were screened against ALR2 as well as aldehyde reductase (ALR1), leading to the discovery of compounds with enhanced ALR2 inhibitory activity and selectivity.

    3. Gadolinium- and Manganite-Based Contrast Agents with Fluorescent Probes for Both Magnetic Resonance and Fluorescence Imaging of Pancreatic Islets: A Comparative Study (pages 614–621)

      Dr. Zuzana Berkova, Dr. Daniel Jirak, Dr. Klara Zacharovova, Prof. Ivan Lukes, Dr. Zuzana Kotkova, Dr. Jan Kotek, Dr. Michal Kacenka, Dr. Ondrej Kaman, Dr. Ivan Rehor, Dr. Milan Hajek and Prof. Frantisek Saudek

      Version of Record online: 11 JAN 2013 | DOI: 10.1002/cmdc.201200439

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      Seeing the light: We evaluated three novel magnetic resonance/fluorescence imaging probes for visualization, cellular distribution, and survival of labeled pancreatic islets in vitro and in vivo. One of these contrast agents, based on perovskite-like manganite nanoparticles, was shown to provide better contrast enhancement within a shorter scan time than existing agents, indicating potential utility for future imaging of transplanted pancreatic islets.

    4. Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors (pages 622–632)

      Dr. Suazette Reid Mooring, Dr. Jin Liu, Dr. Zhongxing Liang, Jeffrey Ahn, Samuel Hong, Dr. Younghyoun Yoon, Dr. James P. Snyder and Dr. Hyunsuk Shim

      Version of Record online: 6 MAR 2013 | DOI: 10.1002/cmdc.201200582

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      Running interference: A series of sulfonamide analogues were synthesized by modification of the tunable area around the previously synthesized potent dipyridine 1. Several of these analogues inhibit the CXCR4–CXCL12 interaction, and are suitable leads for the development of anti-metastasis agents.

    5. A Concise Synthesis of Pyrazole Analogues of Combretastatin A1 as Potent Anti-Tubulin Agents (pages 633–643)

      Dr. Roberta Zaninetti, Salvatore V. Cortese, Dr. Silvio Aprile, Dr. Alberto Massarotti, Prof. Pier Luigi Canonico, Prof. Giovanni Sorba, Prof. Giorgio Grosa, Prof. Armando A. Genazzani and Dr. Tracey Pirali

      Version of Record online: 21 FEB 2013 | DOI: 10.1002/cmdc.201200561

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      (Combreta)statin' the facts: A series of 3,4-diaryl pyrazole analogues of combretastatin A1 were concisely synthesized, one of which proved to be a cytotoxic anti-tubulin agent with low nanomolar potency. It retains the ability to form ortho-quinone species, which are assumed to be directly cytotoxic in tumor cells, while the pyrazole ring shows high metabolic stability, suggesting that this compound might give better pharmacokinetic profiles than the parent compound, with similar pharmacodynamic properties and clinical potential.

    6. The Discovery of Novel Human Androgen Receptor Antagonist Chemotypes Using a Combined Pharmacophore Screening Procedure (pages 644–651)

      Dr. Arnout Voet, Dr. Christine Helsen, Prof. Dr. Kam Y. J. Zhang and Prof. Dr. Frank Claessens

      Version of Record online: 21 FEB 2013 | DOI: 10.1002/cmdc.201200549

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      A new tack altogether: Using structural information for human androgen receptor (hAR) antagonists in an agonistic conformation, a pharmacophore query was constructed for the agonistic and antagonistic conformations. A homology model of hAR in an antagonistic conformation was created. These models were combined for virtual screening to identify pure antagonists, which were experimentally confirmed.

    7. 3-Aryl-4-methyl-2-quinolones Targeting Multiresistant Staphylococcus aureus Bacteria (pages 652–657)

      Anne Doléans-Jordheim, Jean-Baptiste Veron, Olivier Fendrich, Emmanuelle Bergeron, Adrien Montagut-Romans, Yung-Sing Wong, Bianca Furdui, Jean Freney, Charles Dumontet and Ahcène Boumendjel

      Version of Record online: 21 FEB 2013 | DOI: 10.1002/cmdc.201200551

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      Stop the resistance! 3-Aryl-4-methyl-2-quinolones are NorA efflux pump inhibitors that are able to restore the sensitivity of resistant Staphylococcus aureus bacteria toward fluoroquinolones. The most active compound is nontoxic, can be easily prepared in two steps, and shows intrinsic antibacterial activity.

    8. 3-Hydroxyazetidine Carboxylic Acids: Non-Proteinogenic Amino Acids for Medicinal Chemists (pages 658–666)

      Andreas F. G. Glawar, Dr. Sarah F. Jenkinson, Dr. Amber L. Thompson, Shinpei Nakagawa, Prof. Atsushi Kato, Dr. Terry D. Butters and Prof. George W. J. Fleet

      Version of Record online: 6 MAR 2013 | DOI: 10.1002/cmdc.201200541

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      Sweet stability: The synthesis of enantiomers of a 2,4-dideoxy-2,4-iminoribonic acid from D-glucose is the first chemical synthesis of an unprotected 3-hydroxyazetidine-2-carboxylic acid. The N-methylamide derivative is a micromolar inhibitor of β-hexosaminidases, and its enantiomer is a good inhibitor of a β-glucuronidase.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Minireviews
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Case Studies in Modern Drug Discovery and Development. Edited by Xianhai Huang and Robert G. Aslanian (pages 667–668)

      Dr. Thomas Ryckmans

      Version of Record online: 16 JAN 2013 | DOI: 10.1002/cmdc.201300001

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      Wiley, Hoboken 2012. 472 pp., hardcover, $135.00.—ISBN 978-0-470-60181-5

    2. Pharmacogenetics and Individualized Therapy. Edited by Anke-Hilse Maitland-van der Zee and Ann K. Daly (page 668)

      Dr. William Newman

      Version of Record online: 17 JAN 2013 | DOI: 10.1002/cmdc.201300002

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      Wiley, Hoboken 2012. 510 pp., hardcover, $115.00.—ISBN 978-0-470-43354-6

    3. Biopharmaceutics Modeling and Simulations: Theory, Practice, Methods, and Applications. By Kiyohiko Sugano (pages 668–669)

      Dr. Steven C. Sutton

      Version of Record online: 18 JAN 2013 | DOI: 10.1002/cmdc.201300004

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      Wiley, Hoboken 2012. 520 pp., hardcover, $125.00.—ISBN 978-1-1180-2868-1

    4. High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics. By Anatol Kontush and M. John Chapman (pages 669–670)

      Prof. Dmitri Sviridov

      Version of Record online: 25 JAN 2013 | DOI: 10.1002/cmdc.201300008

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      Wiley, Hoboken 2012. 648 pp., hardcover, $135.00.—ISBN 978-0-470-40821-6

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