ChemMedChem

Cover image for Vol. 7 Issue 3

Special Issue: Neuroscience Drug Discovery

March 5, 2012

Volume 7, Issue 3

Pages 337–535

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Editorial
    6. Graphical Abstract
    7. News
    8. Author Profile
    9. Viewpoint
    10. Minireviews
    11. Communications
    12. Full Papers
    13. Book Reviews
    14. Preview
    1. Cover Picture: Discovery of [(2R,5R)-5-{[(5-Fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): A Dual Orexin Receptor Antagonist with Potent Sleep-Promoting Properties (ChemMedChem 3/2012) (page 337)

      Dr. Paul J. Coleman, John D. Schreier, Dr. Christopher D. Cox, Michael J. Breslin, David B. Whitman, Dr. Michael J. Bogusky, Dr. Georgia B. McGaughey, Dr. Rodney A. Bednar, Wei Lemaire, Dr. Scott M. Doran, Steven V. Fox, Susan L. Garson, Dr. Anthony L. Gotter, C. Meacham Harrell, Duane R. Reiss, Dr. Tamara D. Cabalu, Dr. Donghui Cui, Dr. Thomayant Prueksaritanont, Joanne Stevens, Dr. Pamela L. Tannenbaum, Dr. Richard G. Ball, Joyce Stellabott, Dr. Steven D. Young, Dr. George D. Hartman, Dr. Christopher J. Winrow and Dr. John J. Renger

      Version of Record online: 1 MAR 2012 | DOI: 10.1002/cmdc.201290006

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      The cover picture shows orexin neuronal pathways that project from the lateral hypothalamus into regions of the brain that modulate wakefulness. Blockade of this neuropeptide signaling pathway with small-molecule receptor antagonists is a clinically validated approach to the treatment of sleep disorders. The discovery and synthesis of MK-6096 is described in the Full Paper by Paul J. Coleman et al. on p. 415 ff. MK-6096 has as a central core, a piperidine carboxamide with two axial substituents on the piperidine ring. This configuration is essential for high receptor potency and is potentiated by α-methyl substitution on the piperidine ring. MK-6096 is brain penetrant and highly potent in dose-dependently promoting sleep in preclinical electroencephalography (EEG) models.

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Editorial
    6. Graphical Abstract
    7. News
    8. Author Profile
    9. Viewpoint
    10. Minireviews
    11. Communications
    12. Full Papers
    13. Book Reviews
    14. Preview
    1. Inside Cover: Investigation of D2 Receptor–Agonist Interactions Using a Combination of Pharmacophore and Receptor Homology Modeling / Investigation of D1 Receptor–Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling (ChemMedChem 3/2012) (page 338)

      Marcus Malo, Dr. Lars Brive, Prof. Kristina Luthman and Dr. Peder Svensson

      Version of Record online: 1 MAR 2012 | DOI: 10.1002/cmdc.201290007

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      The inside cover picture shows the endogenous neurotransmitter dopamine, the D1 (doxanthrine) and D2 (R-NPA) agonists, and models of their targets (D1 in blue and D2 in yellow). Pharmacophore and homology modeling was used to predict the interactions of these ligands with the dopamine receptors. For more details, see the back-to-back Full Papers by Peder Svensson et al. on p. 471 and 483 ff.

  3. Back Cover

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    5. Editorial
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    1. Inside Back Cover: Chromenopyrazoles: Non-psychoactive and Selective CB1 Cannabinoid Agonists with Peripheral Antinociceptive Properties (ChemMedChem 3/2012) (page 536)

      Dr. Jose Cumella, Dr. Laura Hernández-Folgado, Dr. Rocio Girón, Dr. Eva Sánchez, Paula Morales, Dr. Dow P. Hurst, Maria Gómez-Cañas, Dr. Maria Gómez-Ruiz, Dr. Diana C. G. A. Pinto, Prof. Dr. Pilar Goya, Prof. Dr. Patricia H. Reggio, Prof. Dr. María Isabel Martin, Prof. Dr. Javier Fernández-Ruiz, Prof. Dr. Artur M. S. Silva and Dr. Nadine Jagerovic

      Version of Record online: 1 MAR 2012 | DOI: 10.1002/cmdc.201290011

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      The back cover picture shows a synthetic cannabinoid designed in analogy to cannabinol. It is a selective, full agonist of cannabinoid receptor type 1 (CB1), and molecular modeling studies suggest that the selectivity arises due to the presence of the pyrazole ring. In vivo evaluation ruled out CNS-mediated effects and confirmed antinociception activity. For more details, see the Full Paper by Nadine Jagerovic et al. on p. 452 ff.

  4. Editorial

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      Editorial: Challenges and Opportunities in Neuroscience Research (pages 339–341)

      Dr. Paul J. Coleman and Prof. James C. Barrow

      Version of Record online: 1 MAR 2012 | DOI: 10.1002/cmdc.201200075

  5. Graphical Abstract

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  6. News

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  7. Author Profile

    1. Top of page
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    3. Inside Cover
    4. Back Cover
    5. Editorial
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    1. M. Rarey (page 355)

      Version of Record online: 1 MAR 2012 | DOI: 10.1002/cmdc.201200004

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      A good work day begins with a chat with my secretary telling me that there are no administrative phone calls waiting! My favorite piece of research is Kurt Gödel's incompleteness theorem (1931), because it is one of the very rare cases that a scientist has proven a statement over his research field as a whole. …” This and more about Matthias Rarey can be found on page 355.

  8. Viewpoint

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    5. Editorial
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    11. Communications
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  9. Minireviews

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    1. Modulating Self-Assembly of Amyloidogenic Proteins as a Therapeutic Approach for Neurodegenerative Diseases: Strategies and Mechanisms (pages 359–374)

      Tingyu Liu and Dr. Gal Bitan

      Version of Record online: 9 FEB 2012 | DOI: 10.1002/cmdc.201100585

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      Three strategies—one goal. The major mechanisms of drug candidates is discussed within three broad strategies: 1) stabilizing the monomer, 2) accelerating the pathway, and 3) modulating the pathway towards nontoxic assemblies. The merit of each strategy is assessed, prominent examples are given, and key points to consider when analyzing the efficacy and promise of a drug are discussed.

    2. Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs (pages 375–384)

      Jacques Joubert, Dr. Werner J. Geldenhuys, Prof. Cornelis J. Van der Schyf, Prof. Douglas W. Oliver, Prof.  Hendrik Gert Kruger, Dr. Thavendran Govender and Prof. Sarel F. Malan

      Version of Record online: 3 FEB 2012 | DOI: 10.1002/cmdc.201100559

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      Scaffolds for neuroprotection: Less than five per cent of small-molecule drugs are able to cross the blood–brain barrier (BBB). Developments in the design of compounds incorporating lipophilic, polycyclic structures have been under intense investigation in recent years. Conjugation of privileged moieties and known drug structures to these polycyclic structures has enhanced the delivery of neuroactive drugs across the BBB with subsequent neuroprotective and/or neurorestorative activity.

  10. Communications

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    1. Discovery of Selective Alpha2C Adrenergic Receptor Agonists (pages 385–390)

      Dr. Eric Jnoff, Dr. Bernard Christophe, Philippe Collart, Francis Coloretti, Aurel Debeuckelaere, Dr. Marc De Ryck, Dr. Bruno Fuks, Dr. Christophe Genicot, Dr. Michel Gillard, Dr. Michel Guyaux, Nathalie Price, Marie-Christine Vandergeten and Dr. Céline Vermeiren

      Version of Record online: 19 JAN 2012 | DOI: 10.1002/cmdc.201100528

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      Something to ease the pain: Chemical modification of a 2-amino-oxazoline scaffold led to the identification of α2C adrenergic receptor (AR) agonists. These ligands were characterized by a dual α2C-AR agonist/α2A-AR antagonist profile. Structure–activity relationships were studied, and screening in anesthetized rats demonstrated a superior margin of safety for this class of compounds with respect to cardiovascular effects compared with nonselective α2-AR agonists.

    2. A Benzopyrane Derivative as a P-Glycoprotein Stimulator: A Potential Agent to Decrease β-Amyloid Accumulation in Alzheimer’s Disease (pages 391–395)

      Dr. Marialessandra Contino, Dr. Mariangela Cantore, Dr. Elena Capparelli, Dr. Maria Grazia Perrone, Dr. Mauro Niso, Dr. Carmela Inglese, Prof. Francesco Berardi, Prof. Marcello Leopoldo, Prof. Roberto Perrone and Prof. Nicola Antonio Colabufo

      Version of Record online: 23 DEC 2011 | DOI: 10.1002/cmdc.201100469

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      A simulating interaction: The P-glycoprotein (P-gp) ligand 13 displays high P-gp interacting activity (EC50=2.90 μM) and selectivity in tumor cell lines. Here, this promising compound was further evaluated ex vivo in an everted gut sac assay and found to behave as a P-gp stimulator, making this agent a potential lead for the development of new therapeutics to treat Alzheimer′s disease.

    3. Sulfonimidamides as Sulfonamides Bioisosteres: Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors (pages 396–399)

      Dr. Fernando Sehgelmeble, Dr. Juliette Janson, Dr. Colin Ray, Susanne Rosqvist, Dr. Susanne Gustavsson, Linda I. Nilsson, Dr. Alexander Minidis, Dr. Jörg Holenz, Dr. Didier Rotticci, Dr. Johan Lundkvist and Prof. Dr. Per I. Arvidsson

      Version of Record online: 3 FEB 2012 | DOI: 10.1002/cmdc.201200014

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      The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.

    4. Huprine Derivatives as Sub-Nanomolar Human Acetylcholinesterase Inhibitors: From Rational Design to Validation by X-ray Crystallography (pages 400–405)

      Dr. Cyril Ronco, Dr. Eugénie Carletti, Dr. Jacques-Philippe Colletier, Dr. Martin Weik, Dr. Florian Nachon, Dr. Ludovic Jean and Prof. Pierre-Yves Renard

      Version of Record online: 4 NOV 2011 | DOI: 10.1002/cmdc.201100438

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      This complete study—from rational design to validation by X-ray crystallography—allowed us to discover two sub-nanomolar hAChE inhibitors (430 and 530 pM) grafted with an easily derivatized linker directed toward the AChE peripheral site. The crystal structure of mouse AChE in complex with compound 4 was solved and confirms the favorable position of the triazole in the active site gorge, paving the way for a new class of bifunctional ligands.

    5. Discovery of 2-(2-Benzoxazoyl amino)-4-Aryl-5-Cyanopyrimidine as Negative Allosteric Modulators (NAMs) of Metabotropic Glutamate Receptor 5 (mGlu5): From an Artificial Neural Network Virtual Screen to an In Vivo Tool Compound (pages 406–414)

      Dr. Ralf Mueller, Dr. Eric S. Dawson, Prof. Jens Meiler, Dr. Alice L. Rodriguez, Dr. Brian A. Chauder, Brittney S. Bates, Dr. Andrew S. Felts, Jeffrey P. Lamb, Usha N. Menon, Dr. Sataywan B. Jadhav, Dr. Alexander S. Kane, Prof. Dr. Carrie K. Jones, Dr. Karen J. Gregory, Prof. Colleen M. Niswender, Prof. P. Jeffrey Conn, Dr. Christopher M. Olsen, Prof. Danny G. Winder, Prof. Kyle A. Emmitte and Prof. Craig W. Lindsley

      Version of Record online: 20 JAN 2012 | DOI: 10.1002/cmdc.201100510

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      From ANNs to NAMs! Data from an experimental metabotropic glutamate receptor 5 (mGlu5) high-throughput screen (HTS) were employed to train artificial neural networks (ANNs) based on 345 confirmed negative allosteric modulators (NAMs) and 155 774 inactive compounds. This effort identified two potent mGlu5 NAMs with a unique chemotype. Optimization afforded a tool compound (shown), active in mouse models of anxiety and addiction.

  11. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Editorial
    6. Graphical Abstract
    7. News
    8. Author Profile
    9. Viewpoint
    10. Minireviews
    11. Communications
    12. Full Papers
    13. Book Reviews
    14. Preview
    1. Discovery of [(2R,5R)-5-{[(5-Fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): A Dual Orexin Receptor Antagonist with Potent Sleep-Promoting Properties (pages 415–424)

      Dr. Paul J. Coleman, John D. Schreier, Dr. Christopher D. Cox, Michael J. Breslin, David B. Whitman, Dr. Michael J. Bogusky, Dr. Georgia B. McGaughey, Dr. Rodney A. Bednar, Wei Lemaire, Dr. Scott M. Doran, Steven V. Fox, Susan L. Garson, Dr. Anthony L. Gotter, C. Meacham Harrell, Duane R. Reiss, Dr. Tamara D. Cabalu, Dr. Donghui Cui, Dr. Thomayant Prueksaritanont, Joanne Stevens, Dr. Pamela L. Tannenbaum, Dr. Richard G. Ball, Joyce Stellabott, Dr. Steven D. Young, Dr. George D. Hartman, Dr. Christopher J. Winrow and Dr. John J. Renger

      Version of Record online: 3 FEB 2012 | DOI: 10.1002/cmdc.201200025

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      Exploring DORAs: Orexin receptor antagonism has been identified as a new mechanism for treating insomnia with clinical proof of concept. The design of MK-6096 was partly driven by understanding the conformational properties anticipated to be favorable for high orexin receptor activity. MK-6096 represents a novel therapy for treating insomnia and other disorders related to sleep/wake dysregulation.

    2. Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress (pages 425–439)

      Jay H. Kalin, Dr. Hankun Zhang, Dr. Sophie Gaudrel-Grosay, Dr. Giulio Vistoli and Prof. Alan P. Kozikowski

      Version of Record online: 10 JAN 2012 | DOI: 10.1002/cmdc.201100522

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      Isoform-selective histone deacetylase (HDAC) inhibitors containing mercaptoacetamide zinc binding groups are known to be viable alternatives to the more traditional hydroxamic acid based inhibitors. Herein we demonstrate the HDAC6 enantioselectivity of α-methyl-substituted mercaptoacetamides and provide evidence to support their use as neuroprotective agents.

    3. Structure–Activity Relationships for Negative Allosteric mGluR5 Modulators (pages 440–451)

      Dr. Birgitte H. Kaae, Dr. Kasper Harpsøe, Trine Kvist, Dr. Jesper M. Mathiesen, Christina Mølck, Dr. David Gloriam, Hermogenes N. Jimenez, Michelle A. Uberti, Søren M. Nielsen, Birgitte Nielsen, Prof. Hans Bräuner-Osborne, Per Sauerberg, Dr. Rasmus P. Clausen and Dr. Ulf Madsen

      Version of Record online: 20 JAN 2012 | DOI: 10.1002/cmdc.201100578

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      Exploring a dimeric approach: The design and synthesis of 2-methyl-6-(phenylethynyl)pyridine (MPEP) analogues led to a potent and selective negative modulator of mGluR5. Compounds were characterized at mGluRs and iGluRs; binding and selectivity modes were investigated by homology modeling and docking studies.

    4. Chromenopyrazoles: Non-psychoactive and Selective CB1 Cannabinoid Agonists with Peripheral Antinociceptive Properties (pages 452–463)

      Dr. Jose Cumella, Dr. Laura Hernández-Folgado, Dr. Rocio Girón, Dr. Eva Sánchez, Paula Morales, Dr. Dow P. Hurst, Maria Gómez-Cañas, Dr. Maria Gómez-Ruiz, Dr. Diana C. G. A. Pinto, Prof. Dr. Pilar Goya, Prof. Dr. Patricia H. Reggio, Prof. Dr. María Isabel Martin, Prof. Dr. Javier Fernández-Ruiz, Prof. Dr. Artur M. S. Silva and Dr. Nadine Jagerovic

      Version of Record online: 2 FEB 2012 | DOI: 10.1002/cmdc.201100568

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      Peripheral cannabinoid: Chromenopyrazoles were identified as cannabinoid receptor ligands, and some compounds in the series were found to be selective agonists of the CB1 receptor. Results of molecular modeling studies support this finding. Behavioral tests and peripheral pain assays carried out with the most effective agonist show peripheral analgesia without CNS-mediated effects.

    5. 8-Substituted 3-Arylcoumarins as Potent and Selective MAO-B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies (pages 464–470)

      Dr. Dolores Viña, Dr. Maria J. Matos, Dr. Giulio Ferino, Prof. Enzo Cadoni, Dr. Reyes Laguna, Prof. Fernanda Borges, Prof. Eugenio Uriarte and Prof. Lourdes Santana

      Version of Record online: 27 JAN 2012 | DOI: 10.1002/cmdc.201100538

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      B-selective! With the aim of finding new selective MAO-B inhibitors, herein we report the synthesis, in vitro evaluation, and a docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position as potential inhibitors of hMAO-A and B. Most of the studied compounds have high affinity and selectivity for hMAO-B, with IC50 values in the low micro- to nanomolar range.

    6. You have full text access to this OnlineOpen article
      Investigation of D2 Receptor–Agonist Interactions Using a Combination of Pharmacophore and Receptor Homology Modeling (pages 471–482)

      Marcus Malo, Dr. Lars Brive, Prof. Kristina Luthman and Dr. Peder Svensson

      Version of Record online: 7 FEB 2012 | DOI: 10.1002/cmdc.201100545

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      The magic key for dopamine D2 receptor agonism was studied by using a combined receptor and pharmacophore modeling approach. All available experimental data, including a set of carefully selected active and inactive ligands, were used to identify the reasons behind selectivity and to pinpoint the specific ligand–receptor interactions made by D2 agonists.

    7. You have full text access to this OnlineOpen article
      Investigation of D1 Receptor–Agonist Interactions and D1/D2 Agonist Selectivity Using a Combination of Pharmacophore and Receptor Homology Modeling (pages 483–494)

      Marcus Malo, Dr. Lars Brive, Prof. Kristina Luthman and Dr. Peder Svensson

      Version of Record online: 7 FEB 2012 | DOI: 10.1002/cmdc.201100546

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      The delicate balance between dopamine D1 and D2 agonism was investigated by using our combined receptor and pharmacophore modeling approach described in the preceding paper. Not only can the developed receptor models be used to understand the factors that determine receptor isoform selectivity, but also to design new dopamine receptor-selective agonists for use as potential therapeutic agents.

    8. Arylpiperazine Dopamineric Ligands Protect Neuroblastoma Cells from Nitric Oxide (NO)-Induced Mitochondrial Damage and Apoptosis (pages 495–508)

      Gordana Tovilovic, Dr. Nevena Zogovic, Dr. Ljubica Harhaji-Trajkovic, Maja Misirkic-Marjanovic, Kristina Janjetovic, Ljubica Vucicevic, Dr. Sladjana Kostic-Rajacic, Prof. Andre Schrattenholz, Prof. Aleksandra Isakovic, Prof. Vukic Soskic and Prof. Vladimir Trajkovic

      Version of Record online: 1 FEB 2012 | DOI: 10.1002/cmdc.201100537

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      Guarding the grey matter! Arylpiperazine dopaminergic ligands protect neurons from nitric oxide cytotoxicity. Their ability to modulate cell survival signaling pathways, stabilize mitochondrial membrane, and ultimately prevent neuronal apoptosis, makes them plausible candidates for treatment of neurodegenerative diseases.

    9. Selective Agonists for Dopamine/Neurotensin Receptor Heterodimers (pages 509–514)

      Susanne Koschatzky and Prof. Dr. Peter Gmeiner

      Version of Record online: 23 DEC 2011 | DOI: 10.1002/cmdc.201100499

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      Select the right pair: Radioligand binding studies of the physical interaction between co-expressed dopamine D2L or D3 and neurotensin NTS1 or NTS2 receptors indicate substantial cross-inhibitory effects of both NTS1 and NTS2 receptor subtypes on the agonist binding of D2L or D3 in the presence of neurotensin (NT). D3–NTS2 co-expression gave a 20-fold decrease in affinity for biphenylcarboxamide 5 in the presence of NT.

    10. A Two-Step Strategy for Structure–Activity Relationship Studies of N-Methylated Aβ42 C-Terminal Fragments as Aβ42 Toxicity Inhibitors (pages 515–522)

      Dr. Huiyuan Li, Reeve Zemel, Dr. Dahabada H. J. Lopes, Dr. Bernhard H. Monien and Dr. Gal Bitan

      Version of Record online: 3 FEB 2012 | DOI: 10.1002/cmdc.201100584

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      Step by Step: A two-step N-methyl amino acid substitution method was used for a structure–activity relationship (SAR) study of Aβ(31-42). This strategy provides a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties and metabolic stability.

    11. High-Affinity, Selective σ Ligands of the 1,2,3,4-Tetrahydro-1,4′-silaspiro[naphthalene-1,4′-piperidine] Type: Syntheses, Structures, and Pharmacological Properties (pages 523–532)

      Prof. Dr. Reinhold Tacke, Dr. Rüdiger Bertermann, Dr. Christian Burschka, Steffen Dörrich, Markus Fischer, Dr. Barbara Müller, Géraldine Meyerhans, Dirk Schepmann, Prof. Dr. Bernhard Wünsch, Prof. Dr. Ingvar Arnason and Ragnar Bjornsson

      Version of Record online: 11 NOV 2011 | DOI: 10.1002/cmdc.201100423

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      C/Si switch: We report the syntheses and pharmacological properties of novel silicon analogues of σ ligands of the 1′-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4′-piperidine] type. C/Si exchange leads to a moderate increase in σ1 receptor affinity and to a considerable improvement in σ12 selectivity.

  12. Book Reviews

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    1. The Science and Business of Drug Discovery: Demystifying the Jargon. By Edward D. Zanders. (pages 533–534)

      Prof. Klaus Müller

      Version of Record online: 13 FEB 2012 | DOI: 10.1002/cmdc.201200067

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      Springer, London 2011. xvii+397 pp., hardcover £ 126.00.—ISBN 978-1-4419-9901-6

    2. Chiral Drugs: Chemistry and Biological Action. Edited by Guo-Qiang Lin, Qi-Dong You and Jie-Fei Cheng. (page 534)

      Prof. Thorleif Anthonsen

      Version of Record online: 1 FEB 2012 | DOI: 10.1002/cmdc.201200019

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      John Wiley & Sons, Hoboken 2011. 472 pp., hardcover $ 149.95.—ISBN 978-0-470-58720-1

  13. Preview

    1. Top of page
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    3. Inside Cover
    4. Back Cover
    5. Editorial
    6. Graphical Abstract
    7. News
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    11. Communications
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    1. You have free access to this content
      Preview: ChemMedChem 4/2012 (page 535)

      Version of Record online: 1 MAR 2012 | DOI: 10.1002/cmdc.201290010

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