Jean-Marc Plancher

Publications (13)48.59 Total impact

• Article: Halogen bonding at the active sites of human cathepsin L and MEK1 kinase: efficient interactions in different environments.

  Leo A Hardegger, Bernd Kuhn, Beat Spinnler, Lilli Anselm, Robert Ecabert, Martine Stihle, Bernard Gsell, Ralf Thoma, Joachim Diez, Jörg Benz, Jean-Marc Plancher, Guido Hartmann, Yoshiaki Isshiki, Kenji Morikami, Nobuo Shimma, Wolfgang Haap, David W Banner, François Diederich
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  ABSTRACT: In two series of small-molecule ligands, one inhibiting human cathepsin L (hcatL) and the other MEK1 kinase, biological affinities were found to strongly increase when an aryl ring of the inhibitors is substituted with the larger halogens Cl, Br, and I, but to decrease upon F substitution. X-ray co-crystal structure analyses revealed that the higher halides engage in halogen bonding (XB) with a backbone C=O in the S3 pocket of hcatL and in a back pocket of MEK1. While the S3 pocket is located at the surface of the enzyme, which provides a polar environment, the back pocket in MEK1 is deeply buried in the protein and is of pronounced apolar character. This study analyzes environmental effects on XB in protein-ligand complexes. It is hypothesized that energetic gains by XB are predominantly not due to water replacements but originate from direct interactions between the XB donor (Caryl-X) and the XB acceptor (C=O) in the correct geometry. New X-ray co-crystal structures in the same crystal form (space group P2(1)2(1)2(1)) were obtained for aryl chloride, bromide, and iodide ligands bound to hcatL. These high-resolution structures reveal that the backbone C=O group of Gly61 in most hcatL co-crystal structures maintains water solvation while engaging in XB. An aryl-CF3-substituted ligand of hcatL with an unexpectedly high affinity was found to adopt the same binding geometry as the aryl halides, with the CF3 group pointing to the C=O group of Gly61 in the S3 pocket. In this case, a repulsive F2C-F⋅⋅⋅O=C contact apparently is energetically overcompensated by other favorable protein-ligand contacts established by the CF3 group.
  ChemMedChem 09/2011; 6(11):2048-54. · 3.15 Impact Factor
• Article: Gene expression-based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development.

  Adrian Roth, Franziska Boess, Christian Landes, Guido Steiner, Christian Freichel, Jean-Marc Plancher, Susanne Raab, Cristina de Vera Mudry, Thomas Weiser, Laura Suter
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  ABSTRACT: We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2-week repeat-dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted. A subset of these genes was analyzed in vitro in both rat and human hepatocytes to reveal the potential relevancy of the findings for the situation in humans. This comprehensive analysis of the development compound at the gene expression level allowed interpretation of findings of the follow-up compound in a frontloaded 24-h single-dose acute study that was initiated before regular 2-week repeat-dose studies started. The high similarity of the follow-up compound to the lead compound based on gene expression lead to the immediate termination of the development program for this compound series. Our data demonstrate the value of genomics-based early toxicity prediction in short-term in vivo studies for the characterization of compounds to allow prioritization and selection of suited candidates before compound-, animal-, and cost-intensive longer term studies are undertaken.
  Journal of Biochemical and Molecular Toxicology 05/2011; 25(3):183-94. · 1.38 Impact Factor
• Article: The histamine H₃ receptor as a therapeutic drug target for metabolic disorders: status, challenges and opportunities.

  Jean-Marc Plancher
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  ABSTRACT: Since the histamine-3 receptor (H₃R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H₃R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H₃R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H₃R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H₃R field, together with a brief overview of the clinical trials currently running.
  Current topics in medicinal chemistry 04/2011; 11(12):1430-46. · 4.47 Impact Factor
• Article: Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties

  Hans G. F. Richter, Gregory M. Benson, Konrad H. Bleicher, Denise Blum, Evelyne Chaput, Nicole Clemann, S. Feng, Christophe Gardes, Uwe Grether, Peter Hartmann, Bernd Kuhn, Rainer E. Martin, Jean-Marc Plancher, Markus G. Rudolph, Franz Schuler, Sven Taylor
  Bioorganic & Medicinal Chemistry Letters 02/2011; 21(4):1134-1140. · 2.55 Impact Factor
• Article: Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes.

  Hans G F Richter, Gregory M Benson, Denise Blum, Evelyne Chaput, Song Feng, Christophe Gardes, Uwe Grether, Peter Hartman, Bernd Kuhn, Rainer E Martin, Jean-Marc Plancher, Markus G Rudolph, Franz Schuler, Sven Taylor, Konrad H Bleicher
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  ABSTRACT: Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.
  Bioorganic & medicinal chemistry letters 01/2011; 21(1):191-4. · 2.65 Impact Factor
• Source

  Available from: Bernd Kuhn

  Article: Systematic investigation of halogen bonding in protein-ligand interactions.

  Leo A Hardegger, Bernd Kuhn, Beat Spinnler, Lilli Anselm, Robert Ecabert, Martine Stihle, Bernard Gsell, Ralf Thoma, Joachim Diez, Jörg Benz, Jean-Marc Plancher, Guido Hartmann, David W Banner, Wolfgang Haap, François Diederich
  Angewandte Chemie International Edition 01/2011; 50(1):314-8. · 13.45 Impact Factor
• Article: 5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity.

  Pascale David Pierson, Alec Fettes, Christian Freichel, Silvia Gatti-McArthur, Cornelia Hertel, Jörg Huwyler, Peter Mohr, Toshito Nakagawa, Matthias Nettekoven, Jean-Marc Plancher, Susanne Raab, Hans Richter, Olivier Roche, Rosa María Rodríguez Sarmiento, Monique Schmitt, Franz Schuler, Tadakatsu Takahashi, Sven Taylor, Christoph Ullmer, Ruby Wiegand
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  ABSTRACT: Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds, the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H(3)R inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)-1H-indol-2-yl]methanone 36 are detailed.
  Journal of Medicinal Chemistry 06/2009; 52(13):3855-68. · 4.80 Impact Factor
• Article: Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity: Validation of the Target and Identification of Novel Series

  Pascale David Pierson, Christian Freichel, Silvia Gatti-Mac Arthur, Cornelia Hertel, Jörg Huwyler, Peter Mohr, Toshito Nakagawa, Matthias Nettekoven, Jean-Marc Plancher, Susanne Raab, Hans Richter, Olivier Roche, Rosa María Rodríguez Sarmiento, Monique Schmitt, Franz Schuler, Tadakatsu Takahashi, Sven Taylor, Christoph Ullmer, Ruby Wiegand
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  ABSTRACT: Obesity is a major risk factor for the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. Several pieces of evidence, including data in primates, have demonstrated the beneficial effects of histamine-3 receptor (H3R) inverse agonists in the regulation of food intake and body weight. A pharmacophore model based on selected published H3R ligands and validated by previous investigations, was used to identify the 5-oxy-2-carboxamide-indole core as a novel series of H3R inverse agonists. Extensive structure-activity relationship (SAR) investigations were rewarded by the identification of several compounds reversing (R)-α-methyl-histamine-induced water intake increase and reducing food intake/body weight in rodent models of obesity. Among those compounds, (4,4-difluoro-piperidin-1-yl)-[1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone, selected as a lead compound, was exhibiting a promising profile, including excellent pharmacokinetic properties, good in vitro safety profile and high efficacy in a chronic rodent model of obesity.
  CHIMIA International Journal for Chemistry 04/2009; 63(5):275-278. · 1.21 Impact Factor
• Article: Selective naphthalene H(3) receptor inverse agonists with reduced potential to induce phospholipidosis and their quinoline analogs.

  Rosa María Rodríguez Sarmiento, Matthias H Nettekoven, Sven Taylor, Jean-Marc Plancher, Hans Richter, Olivier Roche
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  ABSTRACT: We reported earlier the refinement of our initial five-point pharmacophore model for the Histamine 3 receptor (H(3)R), with a new acceptor feature important for binding and selectivity against the other histamine receptor subtypes 1, 2 and 4. This approach was validated with a new series of H(3)R inverse agonists: the naphthalene series. In this Letter, we describe our efforts to overcome the phospholipidosis flag identified with our initial lead compound (1a). During the optimization process, we monitored the potency of our molecules toward the H(3) receptor, their selectivity against H(1)R, H(2)R and H(4)R, as well as some key molecular properties that may influence phospholipidosis. Encouraged by the promising profile of the naphthalene series, we used our deeper understanding of the H(3)R pharmacophore model to lead us towards the quinoline series. This series is perceived to have intrinsic advantages with respect to its amphiphilic vector.
  Bioorganic & medicinal chemistry letters 04/2009; 19(15):4495-500. · 2.65 Impact Factor
• Article: Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist.

  Song Feng, Minmin Yang, Zhenshan Zhang, Zhanguo Wang, Di Hong, Hans Richter, Gregory Martin Benson, Konrad Bleicher, Uwe Grether, Rainer E Martin, Jean-Marc Plancher, Bernd Kuhn, Markus Georg Rudolph, Li Chen
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  ABSTRACT: According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved.
  Bioorganic & medicinal chemistry letters 04/2009; 19(9):2595-8. · 2.65 Impact Factor
• Article: Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.

  Leo Alig, Jochem Alsenz, Mirjana Andjelkovic, Stefanie Bendels, Agnès Bénardeau, Konrad Bleicher, Anne Bourson, Pascale David-Pierson, Wolfgang Guba, Stefan Hildbrand, [......], Robert Narquizian, Werner Neidhart, Matthias Nettekoven, Jean-Marc Plancher, Cynthia Rocha, Mark Rogers-Evans, Stephan Röver, Gisbert Schneider, Sven Taylor, Pius Waldmeier
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  ABSTRACT: The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.
  Journal of Medicinal Chemistry 05/2008; 51(7):2115-27. · 5.25 Impact Factor
• Article: Aminothiazole Derivatives as Neuropeptide Y5 Receptor Ligands: Finding the Balance between Affinity and Physicochemical Properties

  Matthias Nettekoven, Wolfgang Guba, Werner Neidhart, Patrizio Mattei, Philippe Pflieger, Jean‐Marc Plancher, Sven Taylor
  ChemMedChem 10/2005; 1(1):45 - 48. · 3.15 Impact Factor
• Article: 5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures

  David Adams, Agnès Bénardeau, Mike J. Bickerdike, Jon M. Bentley, Caterina Bissantz, Anne Bourson, Ian A. Cliffe, Paul Hebeisen, Guy A. Kennett, Antony R. Knight, Craig S. Malcolm, Jacques Mizrahi, Jean-Marc Plancher, Hans Richter, Stephan Röver, Sven Taylor, Steven P. Vickers
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  ABSTRACT: Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. There is increasing evidence suggesting an important role for the 5-HT2C receptor in appetite control. Collaboration between F. Hoffmann-La Roche Ltd and Vernalis Research Ltd has allowed rapid construction of a solid structure-activity relationship around a pyrroloindole core. A one-pot Sonogashira reaction followed by nucleophilic double cyclisation allows an elegant and expedient route to this central motif. Introduction of a (2S)-aminopropyl group in place of the aminoethyl endogenous ligand side-chain enhanced the affinity at the 5-HT2C receptor and reduced affinity towards monoamine oxidase enzymes (MAO). Sulfamidate reagents were found to be very effective for the introduction of the 2-aminopropyl moiety in a stereoselective manner. The substitution at position 5 (indole numbering) was found to be crucial for both affinity and selectivity. Pyrroloindoles bearing an alkoxyether in this position exhibit promising pharmacokinetic parameters in rodent and significant reduction of food intake, after per os application.
  CHIMIA International Journal for Chemistry 08/2004; 58(9):613-620. · 1.21 Impact Factor