Literature DB >> 19875287

Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS.

Ya Zhou1, Alice L Rodriguez, Richard Williams, C David Weaver, P Jeffrey Conn, Craig W Lindsley.   

Abstract

This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype identified by a functional HTS approach. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.

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Year:  2009        PMID： 19875287      PMCID： PMC3177597          DOI： 10.1016/j.bmcl.2009.10.059

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


  27 in total

1.  Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries.

Authors:  William Leister; Kimberly Strauss; David Wisnoski; Zhijian Zhao; Craig Lindsley
Journal:  J Comb Chem       Date:  2003 May-Jun

2.  5-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine: a highly potent, orally active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist with anxiolytic activity.

Authors:  Jeffrey R Roppe; Bowei Wang; Dehua Huang; Lida Tehrani; Theodore Kamenecka; Edwin J Schweiger; Jeffery J Anderson; Jesse Brodkin; Xiaohui Jiang; Merryl Cramer; Janice Chung; Grace Reyes-Manalo; Benito Munoz; Nicholas D P Cosford
Journal:  Bioorg Med Chem Lett       Date:  2004-08-02       Impact factor: 2.823

3.  Expedited SAR study of an mGluR5 antagonists: generation of a focused library using a solution-phase Suzuki coupling methodology.

Authors:  Brian Eastman; Chixu Chen; Nicholas D Smith; Steven Poon; Janice Chung; Grace Reyes-Manalo; Nicholas D P Cosford; Benito Munoz
Journal:  Bioorg Med Chem Lett       Date:  2004-11-15       Impact factor: 2.823

4.  Structure-activity relationships for the linker in a series of pyridinyl-alkynes that are antagonists of the metabotropic glutamate receptor 5 (mGluR5).

Authors:  Peter Bach; Karolina Nilsson; Tor Svensson; Udo Bauer; Lance G Hammerland; Alecia Peterson; Andreas Wållberg; Krister Osterlund; David Karis; Maria Boije; David Wensbo
Journal:  Bioorg Med Chem Lett       Date:  2006-07-11       Impact factor: 2.823

5.  Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes.

Authors:  Tomas de Paulis; Kamondanai Hemstapat; Yelin Chen; Yongqin Zhang; Samir Saleh; David Alagille; Ronald M Baldwin; Gilles D Tamagnan; P Jeffrey Conn
Journal:  J Med Chem       Date:  2006-06-01       Impact factor: 7.446

6.  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

7.  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

8.  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

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

10.  Synthesis and SAR comparison of regioisomeric aryl naphthyridines as potent mGlu5 receptor antagonists.

Authors:  Paul Galatsis; Koji Yamagata; John A Wendt; Cleo J Connolly; John W Mickelson; Jared B J Milbank; Susan E Bove; Christopher S Knauer; Rachel M Brooker; Corinne E Augelli-Szafran; Roy D Schwarz; Jack J Kinsora; Kenneth S Kilgore
Journal:  Bioorg Med Chem Lett       Date:  2007-09-29       Impact factor: 2.823
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  13 in total

Review 1.  Parkinson's disease therapeutics: new developments and challenges since the introduction of levodopa.

Authors:  Yoland Smith; Thomas Wichmann; Stewart A Factor; Mahlon R DeLong
Journal:  Neuropsychopharmacology       Date:  2011-09-28       Impact factor: 7.853

2.  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.

Authors:  Jeffrey P Lamb; Darren W Engers; Colleen M Niswender; Alice L Rodriguez; Daryl F Venable; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2010-12-03       Impact factor: 2.823

3.  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

Review 4.  "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.

Authors:  Michael R Wood; Corey R Hopkins; John T Brogan; P Jeffrey Conn; Craig W Lindsley
Journal:  Biochemistry       Date:  2011-03-04       Impact factor: 3.162

5.  Recent advances in the design and development of novel negative allosteric modulators of mGlu(5).

Authors:  Kyle A Emmitte
Journal:  ACS Chem Neurosci       Date:  2011-08-17       Impact factor: 4.418

6.  (3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu(5): Discovery of a new tool compound with activity in the OSS mouse model of addiction.

Authors:  Craig W Lindsley; Brittney S Bates; Usha N Menon; Satyawan B Jadhav; Alexander S Kane; Carrie K Jones; Alice L Rodriguez; P Jeffrey Conn; Christopher M Olsen; Danny G Winder; Kyle A Emmitte
Journal:  ACS Chem Neurosci       Date:  2011-08-17       Impact factor: 4.418

7.  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

8.  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

9.  Substituted 1-Phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu5: discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction.

Authors:  Russell J Amato; Andrew S Felts; Alice L Rodriguez; Daryl F Venable; Ryan D Morrison; Frank W Byers; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Carrie K Jones; Kyle A Emmitte
Journal:  ACS Chem Neurosci       Date:  2013-05-29       Impact factor: 4.418

10.  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
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