Literature DB >> 21183344

Discovery of molecular switches within the ADX-47273 mGlu5 PAM scaffold that modulate modes of pharmacology to afford potent mGlu5 NAMs, PAMs and partial antagonists.

Jeffrey P Lamb1, Darren W Engers, Colleen M Niswender, Alice L Rodriguez, Daryl F Venable, P Jeffrey Conn, Craig W Lindsley.   

Abstract

This Letter describes a chemical lead optimization campaign directed at a weak mGlu(5) NAM discovered while developing SAR for the mGlu(5) PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu(5) NAMs, mGlu(5) PAMs as well as mGlu(5) partial antagonists.
Copyright © 2010 Elsevier Ltd. All rights reserved.

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Year:  2010        PMID： 21183344      PMCID： PMC3179182          DOI： 10.1016/j.bmcl.2010.11.119

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


  19 in total

Review 1.  Positive and negative allosteric modulation of metabotropic glutamate receptors: emerging therapeutic potential.

Authors:  James N C Kew
Journal:  Pharmacol Ther       Date:  2004-12       Impact factor: 12.310

2.  Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold.

Authors:  Sameer Sharma; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-05-29       Impact factor: 2.823

3.  Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs.

Authors:  Gábor Wágner; Csaba Wéber; Olga Nyéki; Katalin Nógrádi; Attila Bielik; László Molnár; Amrita Bobok; Attila Horváth; Béla Kiss; Sándor Kolok; József Nagy; Dalma Kurkó; Krisztina Gál; István Greiner; Zsolt Szombathelyi; György M Keseru; György Domány
Journal:  Bioorg Med Chem Lett       Date:  2010-04-22       Impact factor: 2.823

4.  3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats.

Authors:  Andrew S Felts; Stacey R Lindsley; Jeffrey P Lamb; Alice L Rodriguez; Usha N Menon; Satyawan Jadhav; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte
Journal:  Bioorg Med Chem Lett       Date:  2010-06-15       Impact factor: 2.823

5.  2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist.

Authors:  F Gasparini; K Lingenhöhl; N Stoehr; P J Flor; M Heinrich; I Vranesic; M Biollaz; H Allgeier; R Heckendorn; S Urwyler; M A Varney; E C Johnson; S D Hess; S P Rao; A I Sacaan; E M Santori; G Veliçelebi; R Kuhn
Journal:  Neuropharmacology       Date:  1999-10       Impact factor: 5.250

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.  Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype.

Authors:  Alice L Rodriguez; Richard Williams; Ya Zhou; Stacey R Lindsley; Uyen Le; Mark D Grier; C David Weaver; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2009-05-03       Impact factor: 2.823

8.  Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology.

Authors:  Alexis S Hammond; Alice L Rodriguez; Steven D Townsend; Colleen M Niswender; Karen J Gregory; Craig W Lindsley; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2010-08-19       Impact factor: 4.418

9.  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

Review 10.  Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

Authors:  P Jeffrey Conn; Arthur Christopoulos; Craig W Lindsley
Journal:  Nat Rev Drug Discov       Date:  2009-01       Impact factor: 84.694
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  25 in total

1.  Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.

Authors:  Bruce J Melancon; Corey R Hopkins; Michael R Wood; Kyle A Emmitte; Colleen M Niswender; Arthur Christopoulos; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2012-01-06       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.  Identification of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Acting at Site Distinct from 2-Methyl-6-(phenylethynyl)-pyridine Binding.

Authors:  Mariusz Butkiewicz; Alice L Rodriguez; Shane E Rainey; Joshua Wieting; Vincent B Luscombe; Shaun R Stauffer; Craig W Lindsley; P Jeffrey Conn; Jens Meiler
Journal:  ACS Chem Neurosci       Date:  2019-06-17       Impact factor: 4.418

Review 4.  Novel Allosteric Modulators of G Protein-coupled Receptors.

Authors:  Patrick R Gentry; Patrick M Sexton; Arthur Christopoulos
Journal:  J Biol Chem       Date:  2015-06-22       Impact factor: 5.157

5.  Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation.

Authors:  Karen J Gregory; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2015-03-25       Impact factor: 4.436

Review 6.  Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).

Authors:  Shaun R Stauffer
Journal:  ACS Chem Neurosci       Date:  2011-06-27       Impact factor: 4.418

7.  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

Review 8.  Drugs for allosteric sites on receptors.

Authors:  Cody J Wenthur; Patrick R Gentry; Thomas P Mathews; Craig W Lindsley
Journal:  Annu Rev Pharmacol Toxicol       Date:  2013-10-02       Impact factor: 13.820

9.  Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site.

Authors:  Karen J Gregory; Elizabeth D Nguyen; Chrysa Malosh; Jeffrey L Mendenhall; Jessica Z Zic; Brittney S Bates; Meredith J Noetzel; Emma F Squire; Eric M Turner; Jerri M Rook; Kyle A Emmitte; Shaun R Stauffer; Craig W Lindsley; Jens Meiler; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2014-02-26       Impact factor: 4.418

10.  Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.

Authors:  Brittney S Bates; Alice L Rodriguez; Andrew S Felts; Ryan D Morrison; Daryl F Venable; Anna L Blobaum; Frank W Byers; Kera P Lawson; J Scott Daniels; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte
Journal:  Bioorg Med Chem Lett       Date:  2014-06-11       Impact factor: 2.823
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