Literature DB >> 26183084

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

Ya Zhou1, Chrysa Malosh1, Susana Conde-Ceide2, Carlos Manuel Martínez-Viturro2, Jesus Alcázar2, Hilde Lavreysen3, Claire Mackie4, Thomas M Bridges1, J Scott Daniels1, Colleen M Niswender1, Carrie K Jones1, Gregor J Macdonald3, Thomas Steckler3, P Jeffrey Conn1, Shaun R Stauffer1, José Manuel Bartolomé-Nebreda5, Craig W Lindsley6.   

Abstract

This Letter describes the progress and challenges in the continued optimization of the mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Entities:  

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

Mesh：

Substances：

Year:  2015        PMID： 26183084      PMCID： PMC4535329          DOI： 10.1016/j.bmcl.2015.06.096

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


  14 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

Review 2.  Section I. The cholinergic system.

Authors:  John Smythies
Journal:  Int Rev Neurobiol       Date:  2005       Impact factor: 3.230

Review 3.  A unique industrial-academic collaboration towards the next generation of schizophrenia therapeutics.

Authors:  Gregor J Macdonald; Craig W Lindsley
Journal:  Curr Top Med Chem       Date:  2014       Impact factor: 3.295

4.  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

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

Authors:  María Luz Martín-Martín; José Manuel Bartolomé-Nebreda; Susana Conde-Ceide; Sergio A Alonso de Diego; Silvia López; Carlos M Martínez-Viturro; Han Min Tong; Hilde Lavreysen; Gregor J Macdonald; Thomas Steckler; Claire Mackie; Thomas M Bridges; J Scott Daniels; Colleen M Niswender; Meredith J Noetzel; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer
Journal:  Bioorg Med Chem Lett       Date:  2015-01-28       Impact factor: 2.823

6.  Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM.

Authors:  Douglas J Sheffler; Cody J Wenthur; Joshua A Bruner; Sheridan J S Carrington; Paige N Vinson; Kiran K Gogi; Anna L Blobaum; Ryan D Morrison; Mitchell Vamos; Nicholas D P Cosford; Shaun R Stauffer; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2012-04-30       Impact factor: 2.823

7.  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

8.  Optimization of an ether series of mGlu5 positive allosteric modulators: molecular determinants of MPEP-site interaction crossover.

Authors:  Jason T Manka; Paige N Vinson; Karen J Gregory; Ya Zhou; Richard Williams; Kiran Gogi; Emily Days; Satya Jadhav; Elizabeth J Herman; Hilde Lavreysen; Claire Mackie; José M Bartolomé; 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:  Bioorg Med Chem Lett       Date:  2012-08-24       Impact factor: 2.823

Review 9.  Allosteric modulators for the treatment of schizophrenia: targeting glutamatergic networks.

Authors:  Frank S Menniti; Craig W Lindsley; P Jeffrey Conn; Jayvardhan Pandit; Panayiotis Zagouras; Robert A Volkmann
Journal:  Curr Top Med Chem       Date:  2013       Impact factor: 3.295

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

1.  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

2.  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
  2 in total

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