Literature DB >> 26157544

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

Susana Conde-Ceide1, Carlos M Martínez-Viturro1, Jesús Alcázar1, Pedro M Garcia-Barrantes2, Hilde Lavreysen3, Claire Mackie3, Paige N Vinson4, Jerri M Rook4, Thomas M Bridges4, J Scott Daniels4, Anton Megens3, Xavier Langlois3, Wilhelmus H Drinkenburg3, Abdellah Ahnaou3, Colleen M Niswender4, Carrie K Jones4, Gregor J Macdonald3, Thomas Steckler3, P Jeffrey Conn4, Shaun R Stauffer4, José Manuel Bartolomé-Nebreda1, Craig W Lindsley4.   

Abstract

Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.

Entities:  

Keywords:  4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine; JNJ-46778212; Positive allosteric modulator (PAM); VU0409551; metabotropic glutamate receptor 5 (mGlu5); schizophrenia

Year:  2015        PMID： 26157544      PMCID： PMC4492464          DOI： 10.1021/acsmedchemlett.5b00181

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


  21 in total

Review 1.  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

2.  Heterotropic activation of the midazolam hydroxylase activity of CYP3A by a positive allosteric modulator of mGlu5: in vitro to in vivo translation and potential impact on clinically relevant drug-drug interactions.

Authors:  Anna L Blobaum; Thomas M Bridges; Frank W Byers; Mark L Turlington; Margrith E Mattmann; Ryan D Morrison; Claire Mackie; Hilde Lavreysen; José M Bartolomé; Gregor J Macdonald; Thomas Steckler; Carrie K Jones; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer; J Scott Daniels
Journal:  Drug Metab Dispos       Date:  2013-09-03       Impact factor: 3.922

Review 3.  The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.

Authors:  D C Goff; J T Coyle
Journal:  Am J Psychiatry       Date:  2001-09       Impact factor: 18.112

Review 4.  Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia.

Authors:  P Jeffrey Conn; Craig W Lindsley; Carrie K Jones
Journal:  Trends Pharmacol Sci       Date:  2008-12-06       Impact factor: 14.819

5.  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 6.  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

7.  A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5.

Authors:  Julie A O'Brien; Wei Lemaire; Tsing-Bau Chen; Raymond S L Chang; Marlene A Jacobson; Sookhee N Ha; Craig W Lindsley; Hervé J Schaffhauser; Cyrille Sur; Douglas J Pettibone; P Jeffrey Conn; David L Williams
Journal:  Mol Pharmacol       Date:  2003-09       Impact factor: 4.436

8.  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

9.  Discovery of N-Aryl Piperazines as Selective mGlu(5) Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity.

Authors:  Ya Zhou; Jason T Manka; Alice L Rodriguez; C David Weaver; Emily L Days; Paige N Vinson; Satyawan Jadhav; Elizabeth J Hermann; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer
Journal:  ACS Med Chem Lett       Date:  2010-08-13       Impact factor: 4.345

10.  Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor.

Authors:  José Manuel Bartolomé-Nebreda; Susana Conde-Ceide; Francisca Delgado; Laura Iturrino; Joaquín Pastor; Miguel Ángel Pena; Andrés A Trabanco; Gary Tresadern; Carola M Wassvik; Shaun R Stauffer; Satyawan Jadhav; Kiran Gogi; Paige N Vinson; Meredith J Noetzel; Emily Days; C David Weaver; Craig W Lindsley; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Frederik Rombouts; Hilde Lavreysen; Gregor J Macdonald; Claire Mackie; Thomas Steckler
Journal:  J Med Chem       Date:  2013-09-04       Impact factor: 7.446
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  18 in total

1.  Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics.

Authors:  Pedro M Garcia-Barrantes; Hyekyung P Cho; Colleen M Niswender; Frank W Byers; Charles W Locuson; Anna L Blobaum; Zixiu Xiang; Jerri M Rook; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2015-10-08       Impact factor: 7.446

Review 2.  Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Authors:  Craig W Lindsley; Kyle A Emmitte; Corey R Hopkins; Thomas M Bridges; Karen J Gregory; Colleen M Niswender; P Jeffrey Conn
Journal:  Chem Rev       Date:  2016-02-16       Impact factor: 60.622

3.  Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery.

Authors:  Kathy Sengmany; Junaid Singh; Gregory D Stewart; P Jeffrey Conn; Arthur Christopoulos; Karen J Gregory
Journal:  Neuropharmacology       Date:  2016-07-05       Impact factor: 5.250

4.  Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.

Authors:  Michael R Wood; Meredith J Noetzel; Bruce J Melancon; Michael S Poslusney; Kellie D Nance; Miguel A Hurtado; Vincent B Luscombe; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Sichen Chang; Michael Bubser; Anna L Blobaum; Darren W Engers; Colleen M Niswender; Carrie K Jones; Nicholas J Brandon; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2016-12-16       Impact factor: 4.345

5.  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

6.  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

7.  Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.

Authors:  Fukang Yang; Lawrence B Snyder; Anand Balakrishnan; Jeffrey M Brown; Digavalli V Sivarao; Amy Easton; Alda Fernandes; Michael Gulianello; Umesh M Hanumegowda; Hong Huang; Yanling Huang; Kelli M Jones; Yu-Wen Li; Michele Matchett; Gail Mattson; Regina Miller; Kenneth S Santone; Arun Senapati; Eric E Shields; Frank J Simutis; Ryan Westphal; Valerie J Whiterock; Joanne J Bronson; John E Macor; Andrew P Degnan
Journal:  ACS Med Chem Lett       Date:  2016-01-04       Impact factor: 4.345

Review 8.  Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders.

Authors:  Daniel J Foster; P Jeffrey Conn
Journal:  Neuron       Date:  2017-05-03       Impact factor: 17.173

9.  Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.

Authors:  Julie L Engers; Katrina A Bollinger; Rebecca L Weiner; Alice L Rodriguez; Madeline F Long; Megan M Breiner; Sichen Chang; Sean R Bollinger; Michael Bubser; Carrie K Jones; Ryan D Morrison; Thomas M Bridges; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2017-08-15       Impact factor: 4.345

Review 10.  Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging.

Authors:  Rajapillai L I Pillai; Dnyanesh N Tipre
Journal:  Eur J Nucl Med Mol Imaging       Date:  2016-01-07       Impact factor: 9.236
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