Literature DB >> 25683622

Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

María Luz Martín-Martín1, José Manuel Bartolomé-Nebreda2, Susana Conde-Ceide2, Sergio A Alonso de Diego2, Silvia López2, Carlos M Martínez-Viturro2, Han Min Tong2, Hilde Lavreysen3, Gregor J Macdonald3, Thomas Steckler3, Claire Mackie4, Thomas M Bridges5, J Scott Daniels5, Colleen M Niswender5, Meredith J Noetzel5, Carrie K Jones5, P Jeffrey Conn5, Craig W Lindsley6, Shaun R Stauffer6.   

Abstract

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Entities:  

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

Mesh：

Substances：

Year:  2015        PMID： 25683622      PMCID： PMC4399811          DOI： 10.1016/j.bmcl.2015.01.038

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


  36 in total

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2.  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

3.  A novel, competitive mGlu(5) receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices.

Authors:  A J Doherty; M J Palmer; Z A Bortolotto; A Hargreaves; A E Kingston; P L Ornstein; D D Schoepp; D Lodge; G L Collingridge
Journal:  Br J Pharmacol       Date:  2000-09       Impact factor: 8.739

4.  Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment.

Authors:  J L Neisewander; D A Baker; R A Fuchs; L T Tran-Nguyen; A Palmer; J F Marshall
Journal:  J Neurosci       Date:  2000-01-15       Impact factor: 6.167

5.  Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254).

Authors:  Mark Turlington; Meredith J Noetzel; Aspen Chun; Ya Zhou; Rocco D Gogliotti; Elizabeth D Nguyen; Karen J Gregory; Paige N Vinson; Jerri M Rook; Kiran K Gogi; Zixiu Xiang; Thomas M Bridges; J Scott Daniels; Carrie Jones; Colleen M Niswender; Jens Meiler; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer
Journal:  J Med Chem       Date:  2013-10-09       Impact factor: 7.446

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.  Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function.

Authors:  G Mannaioni; M J Marino; O Valenti; S F Traynelis; P J Conn
Journal:  J Neurosci       Date:  2001-08-15       Impact factor: 6.167

Review 8.  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

9.  Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex.

Authors:  Lucas Lecourtier; Houman Homayoun; Gilles Tamagnan; Bita Moghaddam
Journal:  Biol Psychiatry       Date:  2007-05-23       Impact factor: 13.382

10.  Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu₅).

Authors:  Mark Turlington; Chrysa Malosh; Jon Jacobs; Jason T Manka; Meredith J Noetzel; Paige N Vinson; Satyawan Jadhav; Elizabeth J Herman; Hilde Lavreysen; Claire Mackie; José M Bartolomé-Nebreda; Susana Conde-Ceide; M Luz Martín-Martín; Han Min Tong; Silvia López; Gregor J MacDonald; Thomas Steckler; J Scott Daniels; C David Weaver; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer
Journal:  J Med Chem       Date:  2014-06-25       Impact factor: 7.446
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  5 in total

1.  Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.

Authors:  Susana Conde-Ceide; Carlos M Martínez-Viturro; Jesús Alcázar; Pedro M Garcia-Barrantes; Hilde Lavreysen; Claire Mackie; Paige N Vinson; Jerri M Rook; Thomas M Bridges; J Scott Daniels; Anton Megens; Xavier Langlois; Wilhelmus H Drinkenburg; Abdellah Ahnaou; Colleen M Niswender; Carrie K Jones; Gregor J Macdonald; Thomas Steckler; P Jeffrey Conn; Shaun R Stauffer; José Manuel Bartolomé-Nebreda; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2015-05-20       Impact factor: 4.345

2.  Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.

Authors:  Ya Zhou; Chrysa Malosh; Susana Conde-Ceide; Carlos Manuel Martínez-Viturro; Jesus Alcázar; Hilde Lavreysen; Claire Mackie; Thomas M Bridges; J Scott Daniels; Colleen M Niswender; Carrie K Jones; Gregor J Macdonald; Thomas Steckler; P Jeffrey Conn; Shaun R Stauffer; José Manuel Bartolomé-Nebreda; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2015-07-04       Impact factor: 2.823

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

Authors:  Chrysa Malosh; Mark Turlington; Thomas M Bridges; Jerri M Rook; Meredith J Noetzel; Paige N Vinson; Thomas Steckler; Hilde Lavreysen; Claire Mackie; José M Bartolomé-Nebreda; Susana Conde-Ceide; Carlos M Martínez-Viturro; María Piedrafita; M Rosa Sánchez-Casado; 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:  2015-10-09       Impact factor: 2.823

4.  Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.

Authors:  Joseph D Panarese; Hykeyung P Cho; Jeffrey J Adams; Kellie D Nance; Pedro M Garcia-Barrantes; Sichen Chang; Ryan D Morrison; Anna L Blobaum; Colleen M Niswender; Shaun R Stauffer; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-04-29       Impact factor: 2.823

5.  Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.

Authors:  Susana Conde-Ceide; Jesús Alcázar; Sergio A Alonso de Diego; Silvia López; María Luz Martín-Martín; Carlos M Martínez-Viturro; Miguel-Angel Pena; Han Min Tong; Hilde Lavreysen; Claire Mackie; Thomas M Bridges; J Scott Daniels; Colleen M Niswender; Carrie K Jones; Gregor J Macdonald; Thomas Steckler; P Jeffrey Conn; Shaun R Stauffer; Craig W Lindsley; José Manuel Bartolomé-Nebreda
Journal:  Bioorg Med Chem Lett       Date:  2015-11-28       Impact factor: 2.823
  5 in total

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