Literature DB >> 22981332

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

Jason T Manka1, 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.   

Abstract

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.
Copyright © 2012 Elsevier Ltd. All rights reserved.

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Year:  2012        PMID： 22981332      PMCID： PMC3755010          DOI： 10.1016/j.bmcl.2012.08.043

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


  32 in total

Review 1.  G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms.

Authors:  Thomas M Bridges; Craig W Lindsley
Journal:  ACS Chem Biol       Date:  2008-07-25       Impact factor: 5.100

2.  Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor.

Authors:  Lichuan Liu; Jason S Halladay; Young Shin; Susan Wong; Melis Coraggio; Hank La; Matthew Baumgardner; Hoa Le; Sashi Gopaul; Jason Boggs; Peter Kuebler; John C Davis; X Charlene Liao; Joseph W Lubach; Alan Deese; C Gregory Sowell; Kevin S Currie; Wendy B Young; S Cyrus Khojasteh; Cornelis E C A Hop; Harvey Wong
Journal:  Drug Metab Dispos       Date:  2011-07-08       Impact factor: 3.922

3.  Design and synthesis of substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides as positive allosteric modulators of the metabotropic glutamate receptor subtype 5.

Authors:  Mu-Fa Zou; Jianjing Cao; Alice L Rodriguez; P Jeffrey Conn; Amy Hauck Newman
Journal:  Bioorg Med Chem Lett       Date:  2010-12-28       Impact factor: 2.823

4.  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

5.  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

6.  Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo.

Authors:  Craig W Lindsley; David D Wisnoski; William H Leister; Julie A O'brien; Wei Lemaire; David L Williams; Maryann Burno; Cyrille Sur; Gene G Kinney; Doug J Pettibone; Philip R Tiller; Sheri Smith; Mark E Duggan; George D Hartman; P Jeffrey Conn; Joel R Huff
Journal:  J Med Chem       Date:  2004-11-18       Impact factor: 7.446

7.  Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine.

Authors:  Pari Malherbe; Nicole Kratochwil; Marie-Thérèse Zenner; Jenny Piussi; Catherine Diener; Claudia Kratzeisen; Christophe Fischer; Richard H P Porter
Journal:  Mol Pharmacol       Date:  2003-10       Impact factor: 4.436

8.  Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines.

Authors:  Sameer Sharma; Jeffrey Kedrowski; Jerri M Rook; Randy L Smith; Carrie K Jones; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2009-07-23       Impact factor: 7.446

9.  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

Review 10.  Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders.

Authors:  Richard M Cleva; M Foster Olive
Journal:  Molecules       Date:  2011-03-02       Impact factor: 4.411
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  7 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.  Probing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology.

Authors:  Karen J Gregory; Elizabeth D Nguyen; Sean D Reiff; Emma F Squire; Shaun R Stauffer; Craig W Lindsley; Jens Meiler; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2013-02-26       Impact factor: 4.436

4.  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

5.  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

6.  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

7.  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
  7 in total

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