Literature DB >> 26475522

Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators.

Chrysa Malosh1, Mark Turlington1, Thomas M Bridges2, Jerri M Rook2, Meredith J Noetzel2, Paige N Vinson2, Thomas Steckler3, Hilde Lavreysen3, Claire Mackie4, José M Bartolomé-Nebreda5, Susana Conde-Ceide5, Carlos M Martínez-Viturro5, María Piedrafita5, M Rosa Sánchez-Casado5, Gregor J Macdonald3, J Scott Daniels2, Carrie K Jones2, Colleen M Niswender2, P Jeffrey Conn2, Craig W Lindsley1, Shaun R Stauffer6.   

Abstract

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM)

Mesh：

Substances：

Year:  2015        PMID： 26475522      PMCID： PMC4634704          DOI： 10.1016/j.bmcl.2015.10.009

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  20 in total

1.  Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus.

Authors:  H Awad; G W Hubert; Y Smith; A I Levey; P J Conn
Journal:  J Neurosci       Date:  2000-11-01       Impact factor: 6.167

2.  Direct interaction enables cross-talk between ionotropic and group I metabotropic glutamate receptors.

Authors:  Julie Perroy; Fabrice Raynaud; Vincent Homburger; Marie-Claude Rousset; Ludovic Telley; Joël Bockaert; Laurent Fagni
Journal:  J Biol Chem       Date:  2008-01-08       Impact factor: 5.157

3.  Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.

Authors:  Jerri M Rook; Meredith J Noetzel; Wendy A Pouliot; Thomas M Bridges; Paige N Vinson; Hyekyung P Cho; Ya Zhou; Rocco D Gogliotti; Jason T Manka; Karen J Gregory; Shaun R Stauffer; F Edward Dudek; Zixiu Xiang; Colleen M Niswender; J Scott Daniels; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn
Journal:  Biol Psychiatry       Date:  2012-11-07       Impact factor: 13.382

4.  Mechanism based neurotoxicity of mGlu5 positive allosteric modulators--development challenges for a promising novel antipsychotic target.

Authors:  Sophie Parmentier-Batteur; Peter H Hutson; Karsten Menzel; Jason M Uslaner; Britta A Mattson; Julie A O'Brien; Brian C Magliaro; Thomas Forest; Craig A Stump; Robert M Tynebor; Neville J Anthony; Thomas J Tucker; Xu-Fang Zhang; Robert Gomez; Sarah L Huszar; Nathalie Lambeng; H Fauré; Emannuel Le Poul; Sonia Poli; Thomas W Rosahl; Jean-Philippe Rocher; Richard Hargreaves; Theresa M Williams
Journal:  Neuropharmacology       Date:  2013-01-02       Impact factor: 5.250

5.  Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator.

Authors:  Holger Rosenbrock; Gert Kramer; Scott Hobson; Eliza Koros; Marc Grundl; Matthias Grauert; Klaus G Reymann; Ulrich H Schröder
Journal:  Eur J Pharmacol       Date:  2010-04-02       Impact factor: 4.432

6.  Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism.

Authors:  Thomas M Bridges; Jerri M Rook; Meredith J Noetzel; Ryan D Morrison; Ya Zhou; Rocco D Gogliotti; Paige N Vinson; Zixiu Xiang; Carrie K Jones; Colleen M Niswender; Craig W Lindsley; Shaun R Stauffer; P Jeffrey Conn; J Scott Daniels
Journal:  Drug Metab Dispos       Date:  2013-07-02       Impact factor: 3.922

7.  Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

Authors:  Jeffrey G Varnes; Andrew P Marcus; Russell C Mauger; Scott R Throner; Valerie Hoesch; Megan M King; Xia Wang; Linda A Sygowski; Nathan Spear; Reto Gadient; Dean G Brown; James B Campbell
Journal:  Bioorg Med Chem Lett       Date:  2011-01-11       Impact factor: 2.823

8.  A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models.

Authors:  Gene G Kinney; Julie A O'Brien; Wei Lemaire; Maryann Burno; Denise J Bickel; Michelle K Clements; Tsing-Bau Chen; David D Wisnoski; Craig W Lindsley; Philip R Tiller; Sheri Smith; Marlene A Jacobson; Cyrille Sur; Mark E Duggan; Douglas J Pettibone; P Jeffrey Conn; David L Williams
Journal:  J Pharmacol Exp Ther       Date:  2004-12-17       Impact factor: 4.030

9.  Discovery and SAR of a novel series of metabotropic glutamate receptor 5 positive allosteric modulators with high ligand efficiency.

Authors:  Mark Turlington; Meredith J Noetzel; Thomas M Bridges; Paige N Vinson; Thomas Steckler; Hilde Lavreysen; Claire Mackie; José M Bartolomé-Nebreda; Susana Conde-Ceide; Han Min Tong; Gregor J Macdonald; J Scott Daniels; Carrie K Jones; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer
Journal:  Bioorg Med Chem Lett       Date:  2014-05-02       Impact factor: 2.823

Review 10.  Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012).

Authors:  Craig W Lindsley; Shaun R Stauffer
Journal:  Pharm Pat Anal       Date:  2013-01
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  2 in total

1.  mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome.

Authors:  Rocco G Gogliotti; Rebecca K Senter; Jerri M Rook; Ayan Ghoshal; Rocio Zamorano; Chrysa Malosh; Shaun R Stauffer; Thomas M Bridges; Jose M Bartolome; J Scott Daniels; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn; Colleen M Niswender
Journal:  Hum Mol Genet       Date:  2016-03-02       Impact factor: 6.150

2.  Are there physicochemical differences between allosteric and competitive ligands?

Authors:  Richard D Smith; Jing Lu; Heather A Carlson
Journal:  PLoS Comput Biol       Date:  2017-11-10       Impact factor: 4.475
  2 in total

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