Literature DB >> 24900255

Benzimidazoles as Potent and Orally Active mGlu5 Receptor Antagonists with an Improved PK Profile.

David Carcache1, Ivo Vranesic2, Joachim Blanz1, Sandrine Desrayaud1, Markus Fendt2, Ralf Glatthar1.   

Abstract

A focused chemical optimization effort of compound 1 based on metabolite elucidation is described, resulting in 15i, a highly potent and selective mGlu5 receptor antagonist with an improved pharmacokinetic profile compared to 1. Characterization of 15i in vivo in the fear-potentiated startle (FPS) paradigm revealed a robust reduction of conditioned fear behavior. This effect nicely correlates with the rat brain pharmacokinetics.

Entities:  

Keywords:  benzimidazoles; mGlu5; pharmacokinetics

Year:  2010        PMID： 24900255      PMCID： PMC4018045          DOI： 10.1021/ml100215b

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  21 in total

1.  The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors.

Authors:  A Pagano; D Ruegg; S Litschig; N Stoehr; C Stierlin; M Heinrich; P Floersheim; L Prezèau; F Carroll; J P Pin; A Cambria; I Vranesic; P J Flor; F Gasparini; R Kuhn
Journal:  J Biol Chem       Date:  2000-10-27       Impact factor: 5.157

2.  Metabotropic glutamate 5 receptor blockade alleviates akinesia by normalizing activity of selective basal-ganglia structures in parkinsonian rats.

Authors:  Nathalie Breysse; Marianne Amalric; Pascal Salin
Journal:  J Neurosci       Date:  2003-09-10       Impact factor: 6.167

Review 3.  Molecular pharmacology and therapeutic prospects of metabotropic glutamate receptor allosteric modulators.

Authors:  Andreas Ritzén; Jesper Mosolff Mathiesen; Christian Thomsen
Journal:  Basic Clin Pharmacol Toxicol       Date:  2005-10       Impact factor: 4.080

4.  ABP688, a novel selective and high affinity ligand for the labeling of mGlu5 receptors: identification, in vitro pharmacology, pharmacokinetic and biodistribution studies.

Authors:  Samuel Hintermann; Ivo Vranesic; Hans Allgeier; Armin Brülisauer; Daniel Hoyer; Michel Lemaire; Thomas Moenius; Stephan Urwyler; Steven Whitebread; Fabrizio Gasparini; Yves P Auberson
Journal:  Bioorg Med Chem       Date:  2006-10-21       Impact factor: 3.641

5.  Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity.

Authors:  Carsten Spanka; Ralf Glatthar; Sandrine Desrayaud; Markus Fendt; David Orain; Thomas Troxler; Ivo Vranesic
Journal:  Bioorg Med Chem Lett       Date:  2009-11-05       Impact factor: 2.823

Review 6.  The neuroanatomical and neurochemical basis of conditioned fear.

Authors:  M Fendt; M S Fanselow
Journal:  Neurosci Biobehav Rev       Date:  1999-05       Impact factor: 8.989

Review 7.  Metabotropic glutamate receptors: novel targets for drug development.

Authors:  T Knöpfel; R Kuhn; H Allgeier
Journal:  J Med Chem       Date:  1995-04-28       Impact factor: 7.446

8.  Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain.

Authors:  R Shigemoto; S Nomura; H Ohishi; H Sugihara; S Nakanishi; N Mizuno
Journal:  Neurosci Lett       Date:  1993-11-26       Impact factor: 3.046

Review 9.  Metabotropic glutamate receptors as novel targets for anxiety and stress disorders.

Authors:  Chad J Swanson; Mark Bures; Michael P Johnson; Anni-Maija Linden; James A Monn; Darryle D Schoepp
Journal:  Nat Rev Drug Discov       Date:  2005-02       Impact factor: 84.694

10.  Profiling of trans-azetidine-2,4-dicarboxylic acid at the human metabotropic glutamate receptors mGlu1b, -2, -4a and -5a.

Authors:  T Knöpfel; J Sakaki; P J Flor; P Baumann; A I Sacaan; G Veliçelebi; R Kuhn; H Allgeier
Journal:  Eur J Pharmacol       Date:  1995-02-15       Impact factor: 4.432
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  2 in total

1.  Recent advances in the design and development of novel negative allosteric modulators of mGlu(5).

Authors:  Kyle A Emmitte
Journal:  ACS Chem Neurosci       Date:  2011-08-17       Impact factor: 4.418

2.  Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.

Authors:  Andrew S Felts; Katrina A Bollinger; Christopher J Brassard; Alice L Rodriguez; Ryan D Morrison; J Scott Daniels; Anna L Blobaum; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2018-11-10       Impact factor: 2.823
  2 in total

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