ChemMedChem

Cover image for Vol. 7 Issue 10

Special Issue: Ion Channel Drug Discovery

October 2012

Volume 7, Issue 10

Pages 1693–1863

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      Cover Picture: Identification of Selective Inhibitors of the Potassium Channel Kv1.1–1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp (ChemMedChem 10/2012) (page 1693)

      Sören J. Wacker, Dr. Wiktor Jurkowski, Dr. Katie J. Simmons, Prof. Dr. Colin W. G. Fishwick, Prof. Dr. A. Peter Johnson, Dr. David Madge, Prof. Dr. Erik Lindahl, Dr. Jean-Francois Rolland and Prof. Dr. Bert L. de Groot

      Article first published online: 24 SEP 2012 | DOI: 10.1002/cmdc.201290047

      Thumbnail image of graphical abstract

      The front cover picture shows the potassium channel Kv1.2 together with a Kv1.2-blocking compound. The background color indicates the environment—Blue stands for water and yellow for the lipid bilayer. Only three subunits of the Kv1.2 tetramer are depicted. Atoms of the selectivity filter are shown in stick representation, and water and potassium ions in the filter as spheres. Beneath the filter, in the cavity, a potassium-channel-blocking compound is modeled. The lower right box shows the cavity in more detail. The mesh indicates the cavity's shape. Green carbon atoms belong to the potassium channel. Targeting this site with molecular docking, we identified 14 novel Kv1.2-blocking compounds. For more details, see the Full Paper by Jean-Francois Rolland, Bert L. de Groot et al. on p. 1775 ff.

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      Inside Cover: Structure–Activity Relationships of a Novel Group of Large-Conductance Ca2+-Activated K+ (BK) Channel Modulators: The GoSlo-SR Family (ChemMedChem 10/2012) (page 1694)

      Subhrangsu Roy, Adebola Morayo Akande, Roddy J. Large, Tim I. Webb, Costin Camarasu, Gerard P. Sergeant, Noel G. McHale, Keith D. Thornbury and Mark A. Hollywood

      Article first published online: 24 SEP 2012 | DOI: 10.1002/cmdc.201290048

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      The inside cover picture shows two members of the GoSlo-SR family of BK channel modulators that activate channels at physiological potentials. These were developed by the Smooth Muscle Research and Ion Channel Biotechnology Centres in Ireland and may form a scaffold for the future development of smooth-muscle-specific relaxants to help treat overactive bladder, hypertension or asthma. For more details, see the Communication by Mark A. Hollywood et al. on p. 1763 ff.

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    1. Back Cover: Selective Modification of the N-Terminal Structure of Polytheonamide B Significantly Changes its Cytotoxicity and Activity as an Ion Channel (ChemMedChem 10/2012) (page 1864)

      Dr. Naoki Shinohara, Hiroaki Itoh, Dr. Shigeru Matsuoka and Prof. Dr. Masayuki Inoue

      Article first published online: 24 SEP 2012 | DOI: 10.1002/cmdc.201290052

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      The back cover picture shows the helical structure of naturally occurring polypeptide polytheonamide B, a potent cytotoxic agent that acts as a monovalent cation channel. Evaluation of synthetic derivatives suggests that the peptide's intrinsic activities can only be altered by switching the N-terminal substitution. For more details, see the Communication by Masayuki Inoue et al. on p. 1770 ff.

  3. Editorial

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      Editorial: Channeling Drug Discovery (pages 1695–1697)

      Dr. Henning Steinhagen and Dr. Nils Damann

      Article first published online: 24 SEP 2012 | DOI: 10.1002/cmdc.201200416

  4. Graphical Abstract

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    1. Graphical Abstract: ChemMedChem 10/2012 (pages 1699–1703)

      Article first published online: 24 SEP 2012 | DOI: 10.1002/cmdc.201290049

  5. News

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  6. Review

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    1. Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules (pages 1712–1740)

      Dr. Antonio Nardi, Dr. Nils Damann, Dr. Torsten Hertrampf and Dr. Achim Kless

      Article first published online: 4 SEP 2012 | DOI: 10.1002/cmdc.201200298

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      Nav1 in the crosshairs: Herein we review the current state of the art in voltage-gated sodium channels as drug targets, including the molecular mechanisms that underlie sodium channel modulators. Recent developments in drug discovery aimed at the identification of a new generation of small-molecule inhibitors, including the pharmacological exploitation of other binding sites, are also discussed.

      Corrected by:

      Corrigendum: Corrigendum: Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules

      Vol. 7, Issue 11, 1874, Article first published online: 29 OCT 2012

  7. Minireview

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    1. Trafficking of Intermediate (KCa3.1) and Small (KCa2.x) Conductance, Ca2+-Activated K+ Channels: a Novel Target for Medicinal Chemistry Efforts? (pages 1741–1755)

      Dr. Corina M. Balut, Dr. Kirk L. Hamilton and Prof. Daniel C. Devor

      Article first published online: 7 AUG 2012 | DOI: 10.1002/cmdc.201200226

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      Traffic control: KCa3.1 and KCa2.x channels are very distinct with respect to their localization and lifetime at the plasma membrane, and exhibit unique trafficking itineraries. Deciphering the molecular mechanisms of KCa trafficking events is expected to bring into focus potential candidates for drug therapies with beneficial effects in the disease states related to these channels.

  8. Concept

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    1. Ion Channel Phosphorylopathy: a Link between Genomic Variation and Human Disease (pages 1757–1761)

      Dr. Saverio Gentile

      Article first published online: 24 AUG 2012 | DOI: 10.1002/cmdc.201200236

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      The wide-ranging effects of phosphorylopathies imply the involvement of large and complex biomolecular networks. As modern medicine focuses increasingly on the dysregulation of cellular protein networks rather than the malfunction of single proteins, understanding ion channel phosphorylopathies would provide a compelling opportunity to develop multifaceted strategies focused on signal transduction therapy.

  9. Communications

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    1. Structure–Activity Relationships of a Novel Group of Large-Conductance Ca2+-Activated K+ (BK) Channel Modulators: The GoSlo-SR Family (pages 1763–1769)

      Subhrangsu Roy, Adebola Morayo Akande, Roddy J. Large, Tim I. Webb, Costin Camarasu, Gerard P. Sergeant, Noel G. McHale, Keith D. Thornbury and Mark A. Hollywood

      Article first published online: 28 AUG 2012 | DOI: 10.1002/cmdc.201200321

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      Opening up ion channels: We synthesised a series of anthraquinone analogues, called the GoSlo-SR family. Their effects on bladder smooth muscle BK channels were examined and, as shown, shifted voltage dependent activation >−100 mV (at 10 μM). They were more efficacious than NS11021 and could provide a new scaffold for the design of efficacious BK openers.

    2. Selective Modification of the N-Terminal Structure of Polytheonamide B Significantly Changes its Cytotoxicity and Activity as an Ion Channel (pages 1770–1773)

      Dr. Naoki Shinohara, Hiroaki Itoh, Dr. Shigeru Matsuoka and Prof. Dr. Masayuki Inoue

      Article first published online: 4 APR 2012 | DOI: 10.1002/cmdc.201200142

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      Chemical point mutation: Polytheonamide B is a naturally occurring polypeptide containing 48 amino acids. It both displays potent cytotoxicity and acts as a monovalent cation channel in vitro. Chemoselective methods to modify the 44th, N-, and C-terminal residues of the natural product have been developed, and evaluation of the resultant derivatives suggests that the intrinsic activities of the peptide can only be altered by switching its N-terminal substitution.

  10. Full Papers

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    4. Editorial
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    1. You have full text access to this OnlineOpen article
      Identification of Selective Inhibitors of the Potassium Channel Kv1.1–1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp (pages 1775–1783)

      Sören J. Wacker, Dr. Wiktor Jurkowski, Dr. Katie J. Simmons, Prof. Dr. Colin W. G. Fishwick, Prof. Dr. A. Peter Johnson, Dr. David Madge, Prof. Dr. Erik Lindahl, Dr. Jean-Francois Rolland and Prof. Dr. Bert L. de Groot

      Article first published online: 30 MAR 2012 | DOI: 10.1002/cmdc.201100600

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      Show me some ID: Lead compounds as potassium channel Kv1.1–1.2(3) inhibitors were identified by structure-based virtual screening and automated patch clamp. The inner cavity of Kv1.1–1.2(3) was subjected to a target-specific and consensus-based molecular docking approach, and 14 active compounds (IC50: 0.6–6 μM) were identified. Two of these are at least 30-fold more potent against Kv1.1-1.2(3) than toward a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), yielding a profile of selectivity and cardiac safety.

    2. Calcium- and Voltage-Gated Potassium (BK) Channel Activators in the 5β-Cholanic Acid-3α-ol Analogue Series with Modifications in the Lateral Chain (pages 1784–1792)

      Dr. Anna N. Bukiya, Dr. Shivaputra A. Patil, Dr. Wei Li, Prof. Duane D. Miller and Prof. Alex M. Dopico

      Article first published online: 4 SEP 2012 | DOI: 10.1002/cmdc.201200290

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      Nothing is that simple: We investigated the structure–activity relationship for analogues of lithocholic acid with modifications to the length and substituents of the lateral chain, unveiling new activators of smooth muscle BK channel. Terminal substituents with an overall negative net charge and lateral chains with a small volume were found to be optimal. These observations will be useful for the design of BK channel activators with potential application in the treatment of hypertension, asthma, and other disorders.

    3. Structural and Pharmacological Characterization of Phenylalanine-Based AMPA Receptor Antagonists at Kainate Receptors (pages 1793–1798)

      Dr. Raminta Venskutonytė, Prof. Karla Frydenvang, Elena Antón Valadés, Dr. Ewa Szymańska, Prof. Tommy N. Johansen, Prof. Jette S. Kastrup and Prof. Darryl S. Pickering

      Article first published online: 7 MAR 2012 | DOI: 10.1002/cmdc.201100599

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      Control your KAR: A series of phenylalanine derivatives act as kainate receptor (KAR) antagonists at non-desensitizing GluK1 and GluK3. As GluK3-selective antagonists are highly desirable within KAR research, compound 3 d, combined with the crystal structure of (S)-3 h in the GluK1 ligand binding domain, might serve as a starting point for the development of improved phenylalanine-based compounds.

    4. Asymmetric 4-Aryl-1,4-dihydropyridines Potentiate Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) (pages 1799–1807)

      Dr. Michele Giampieri, Dr. Nicolas Vanthuyne, Dr. Erika Nieddu, Dr. Marco T. Mazzei, Dr. Maria Anzaldi, Dr. Nicoletta Pedemonte, Dr. Luis J. V. Galietta, Prof. Christian Roussel and Prof. Mauro Mazzei

      Article first published online: 27 AUG 2012 | DOI: 10.1002/cmdc.201200311

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      The racemate for a cure: 1,4-Dihydropyridines (DHPs) are already known as potential drugs for cystic fibrosis caused by class III mutations. Asymmetric DHPs were synthesized and tested as racemates on Fischer rat thyroid cells expressing three mutations. Some DHPs are effective potentiators at the nanomolar level. The most active DHPs (e.g., 4 c) were subjected to chiral separation and retested, but the resulting difference in activity between enantiomers was modest.

    5. Gram-Scale Solution-Phase Synthesis of Selective Sodium Bicarbonate Co-transport Inhibitor S0859: in vitro Efficacy Studies in Breast Cancer Cells (pages 1808–1814)

      Ann M. Larsen, Dr. Niels Krogsgaard-Larsen, Gitte Lauritzen, Christina W. Olesen, Prof. Steen Honoré Hansen, Dr. Ebbe Boedtkjer, Prof. Stine F. Pedersen and Prof. Lennart Bunch

      Article first published online: 27 AUG 2012 | DOI: 10.1002/cmdc.201200335

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      Big news on NBC: The N-cyanosulfonamide S0859 has been shown to inhibit the Na+-coupled HCO3 transporter (NBC)-mediated transport of HCO3 across cell membranes. NBCs are ubiquitous regulators of intracellular pH, and their dysregulation is associated with a range of diseases. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials.

    6. Synthesis and Biological Evaluation of ortho-Aryl N-Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform-Selective Inhibitors (pages 1815–1824)

      Dr. Wei-Jan Huang, Dr. Yi-Ching Wang, Shi-Wei Chao, Chen-Yui Yang, Liang-Chieh Chen, Dr. Mei-Hsiang Lin, Dr. Wen-Chi Hou, Mei-Yu Chen, Tai-Lin Lee, Ping Yang and Dr. Chung-I Chang

      Article first published online: 20 AUG 2012 | DOI: 10.1002/cmdc.201200300

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      Spec-HDAC-ular! Several ortho-aryl N-hydroxycinnamides with potent HDAC8 inhibitory activity were synthesized by knowledge-based design combined with molecular modeling techniques. One compound, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (22 d), exhibited higher cellular effects than PCI34051 on several human lung cancer cells. The results suggest that this compound may be used as a tool to probe the physiological role of HDAC8.

    7. Design and Synthesis of 3-Carbamoylbenzoic Acid Derivatives as Inhibitors of Human Apurinic/Apyrimidinic Endonuclease 1 (APE1) (pages 1825–1839)

      Dr. Francesca Aiello, Yumna Shabaik, Adrian Esqueda, Tino W. Sanchez, Dr. Fedora Grande, Prof. Antonio Garofalo and Prof. Nouri Neamati

      Article first published online: 5 SEP 2012 | DOI: 10.1002/cmdc.201200334

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      Cancer in disrepair: The base-excision repair (BER) pathway is the foremost pathway responsible for removal and replacement of damaged DNA bases. Several BER enzymes have altered expression and activation in cancer cells, and among them APE1 has emerged as a particularly attractive target for anticancer drug development, as demonstrated by studies that link its overexpression with resistance to radio- and chemotherapy.

    8. Synthesis and Cytotoxicity of Three trans-Palladium Complexes Containing Planaramine Ligands in Human Ovarian Tumor Models (pages 1840–1846)

      Mohammed Ehsanul Hoque Mazumder, Philip Beale, Charles Chan, Jun Qing Yu and Prof. Fazlul Huq

      Article first published online: 16 AUG 2012 | DOI: 10.1002/cmdc.201200310

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      Tuning reactivity: Three trans-planaraminepalladium(II) complexes were synthesized and characterized for their activity against cisplatin-sensitive and resistant human ovarian cancer cell lines. All three were found to be less active than the reference compound cisplatin, but unlike cisplatin, they were found to be equally or more active against the resistant cell lines A2780cisR and A2780ZD0473R than against the parent cell line A2780.

    9. 2-Aminopyridine Derivatives as Potential σ2 Receptor Antagonists (pages 1847–1857)

      Dr. Carmen Abate, Prof. Savina Ferorelli, Dr. Mauro Niso, Dr. Cesarea Lovicario, Dr. Vittoria Infantino, Dr. Paolo Convertini, Prof. Dr. Roberto Perrone and Prof. Dr. Francesco Berardi

      Article first published online: 13 AUG 2012 | DOI: 10.1002/cmdc.201200246

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      A reduced fat option: N-Cyclohexylpiperazine derivatives linked to a 2-aminopyridine moiety were generated as less lipophilic analogues of the σ2 agonist PB28. The new N-cyclohexylpiperazines, which display high affinity for σ subtypes, are devoid of antiproliferative activity and may be proposed as σ2 receptor antagonists.

  11. Book Reviews

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    1. Kinase Drug Discovery. Edited by Richard A. Ward and Frederick W. Goldberg. (pages 1858–1859)

      Prof. Richard Engh

      Article first published online: 16 MAY 2012 | DOI: 10.1002/cmdc.201200231

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      RSC, Cambridge 2011. 332 pp., hardcover £ 132.99.—ISBN 978-1-84973-174-4

    2. Neglected Diseases and Drug Discovery. Edited by Michael J. Palmer and Timothy N. C. Wells. (page 1859)

      Prof. Ian Gilbert

      Article first published online: 21 MAY 2012 | DOI: 10.1002/cmdc.201200232

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      RSC, Cambridge 2011. 458 pp., hardcover £ 132.99.—ISBN 978-1-84973-192-8

    3. Polyamine Drug Discovery. Edited by Patrick Woster and Robert A. Casero, Jr. (pages 1859–1860)

      Prof. Raphaël Tripier

      Article first published online: 19 JUN 2012 | DOI: 10.1002/cmdc.201200294

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      RSC, Cambridge 2011. 302 pp., hardcover £ 132.99.—ISBN 978-1-84973-190-4

    4. Drug Delivery in Oncology. Edited by Felix Kratz, Peter Senter and Henning Steinhagen. (pages 1860–1862)

      Prof. Rosa María Olmo López

      Article first published online: 22 AUG 2012 | DOI: 10.1002/cmdc.201200357

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      Wiley-VCH, Weinheim 2011. 1690 pp., hardcover € 449.00.—ISBN 978-3-527-32823-9

  12. Preview

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      Preview: ChemMedChem 11/2012 (page 1863)

      Article first published online: 24 SEP 2012 | DOI: 10.1002/cmdc.201290051

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