Literature DB >> 26684851

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.

Susana Conde-Ceide1, Jesús Alcázar1, Sergio A Alonso de Diego1, Silvia López1, María Luz Martín-Martín1, Carlos M Martínez-Viturro1, Miguel-Angel Pena1, Han Min Tong1, Hilde Lavreysen2, Claire Mackie3, Thomas M Bridges4, J Scott Daniels4, Colleen M Niswender4, Carrie K Jones4, Gregor J Macdonald2, Thomas Steckler2, P Jeffrey Conn4, Shaun R Stauffer4, Craig W Lindsley5, José Manuel Bartolomé-Nebreda6.   

Abstract

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Metabotropic glutamate receptor; N-Methyl-d-aspartate (NMDA); Positive allosteric modulator (PAM); Schizophrenia; mGlu(5)

Mesh：

Substances：

Year:  2015        PMID： 26684851      PMCID： PMC4835042          DOI： 10.1016/j.bmcl.2015.11.098

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


  24 in total

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Review 2.  Targeting glutamate synapses in schizophrenia.

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3.  Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Authors:  Jerri M Rook; Zixiu Xiang; Xiaohui Lv; Ayan Ghoshal; Jonathan W Dickerson; Thomas M Bridges; Kari A Johnson; Daniel J Foster; Karen J Gregory; Paige N Vinson; Analisa D Thompson; Nellie Byun; Rebekah L Collier; Michael Bubser; Michael T Nedelcovych; Robert W Gould; Shaun R Stauffer; J Scott Daniels; Colleen M Niswender; Hilde Lavreysen; Claire Mackie; Susana Conde-Ceide; Jesus Alcazar; José M Bartolomé-Nebreda; Gregor J Macdonald; John C Talpos; Thomas Steckler; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn
Journal:  Neuron       Date:  2015-04-30       Impact factor: 17.173

4.  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

5.  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

6.  Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator.

Authors:  Nathan Spear; Reto A Gadient; Deidre E Wilkins; MyLinh Do; Jeffrey S Smith; Kim L Zeller; Patricia Schroeder; Minli Zhang; Jalaj Arora; Vijay Chhajlani
Journal:  Eur J Pharmacol       Date:  2011-02-16       Impact factor: 4.432

7.  In vitro characterisation of the novel positive allosteric modulators of the mGlu₅ receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat.

Authors:  Gary Gilmour; Lisa M Broad; Keith A Wafford; Thomas Britton; Ellen M Colvin; Adam Fivush; Francois Gastambide; Brian Getman; Beverly A Heinz; Andrew P McCarthy; Lourdes Prieto; Elaine Shanks; Janice W Smith; Lorena Taboada; Dale M Edgar; Mark D Tricklebank
Journal:  Neuropharmacology       Date:  2012-08-01       Impact factor: 5.250

8.  N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement.

Authors:  K J Gregory; E J Herman; A J Ramsey; A S Hammond; N E Byun; S R Stauffer; J T Manka; S Jadhav; T M Bridges; C D Weaver; C M Niswender; T Steckler; W H Drinkenburg; A Ahnaou; H Lavreysen; G J Macdonald; J M Bartolomé; C Mackie; B J Hrupka; M G Caron; T L Daigle; C W Lindsley; P J Conn; C K Jones
Journal:  J Pharmacol Exp Ther       Date:  2013-08-21       Impact factor: 4.030

9.  Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release.

Authors:  Houman Homayoun; Mark R Stefani; Barbara W Adams; Gilles D Tamagan; Bita Moghaddam
Journal:  Neuropsychopharmacology       Date:  2004-07       Impact factor: 7.853

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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  2 in total

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Authors:  Adam C Mar; Simon R O Nilsson; Begoña Gamallo-Lana; Ming Lei; Theda Dourado; Johan Alsiö; Lisa M Saksida; Timothy J Bussey; Trevor W Robbins
Journal:  Psychopharmacology (Berl)       Date:  2017-07-26       Impact factor: 4.530

Review 2.  Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.

Authors:  Deborah J Luessen; P Jeffrey Conn
Journal:  Pharmacol Rev       Date:  2022-07       Impact factor: 18.923
  2 in total

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