Literature DB >> 18550372

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

Sameer Sharma1, Alice L Rodriguez, P Jeffrey Conn, Craig W Lindsley.   

Abstract

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a mGluR5 allosteric partial antagonist lead based on a 5-(phenylethynyl)pyrimidine scaffold. With slight structural modifications to the distal phenyl ring, analogues demonstrated a range of pharmacological activities from mGluR5 partial antagonism to full antagonism/negative allosteric modulation to positive allosteric modulation.

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Year:  2008        PMID： 18550372      PMCID： PMC2533619          DOI： 10.1016/j.bmcl.2008.05.091

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


  15 in total

Review 1.  Pharmacological agents acting at subtypes of metabotropic glutamate receptors.

Authors:  D D Schoepp; D E Jane; J A Monn
Journal:  Neuropharmacology       Date:  1999-10       Impact factor: 5.250

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

Review 3.  Discovery of positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5).

Authors:  David L Williams; Craig W Lindsley
Journal:  Curr Top Med Chem       Date:  2005       Impact factor: 3.295

Review 4.  Application of combinatorial chemistry science on modern drug discovery.

Authors:  J Phillip Kennedy; Lyndsey Williams; Thomas M Bridges; R Nathan Daniels; David Weaver; Craig W Lindsley
Journal:  J Comb Chem       Date:  2008-01-26

Review 5.  Pharmacology and functions of metabotropic glutamate receptors.

Authors:  P J Conn; J P Pin
Journal:  Annu Rev Pharmacol Toxicol       Date:  1997       Impact factor: 13.820

6.  Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity.

Authors:  Richard H P Porter; Georg Jaeschke; Will Spooren; Theresa M Ballard; Bernd Büttelmann; Sabine Kolczewski; Jens-Uwe Peters; Eric Prinssen; Jürgen Wichmann; Eric Vieira; Andreas Mühlemann; Silvia Gatti; Vincent Mutel; Pari Malherbe
Journal:  J Pharmacol Exp Ther       Date:  2005-07-22       Impact factor: 4.030

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.  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

9.  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

10.  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
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  44 in total

1.  Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity.

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Journal:  Mol Pharmacol       Date:  2010-10-05       Impact factor: 4.436

2.  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

3.  Discovery of 2-(2-benzoxazoyl amino)-4-aryl-5-cyanopyrimidine as negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu₅): from an artificial neural network virtual screen to an in vivo tool compound.

Authors:  Ralf Mueller; Eric S Dawson; Jens Meiler; Alice L Rodriguez; Brian A Chauder; Brittney S Bates; Andrew S Felts; Jeffrey P Lamb; Usha N Menon; Sataywan B Jadhav; Alexander S Kane; Carrie K Jones; Karen J Gregory; Colleen M Niswender; P Jeffrey Conn; Christopher M Olsen; Danny G Winder; Kyle A Emmitte; Craig W Lindsley
Journal:  ChemMedChem       Date:  2012-01-20       Impact factor: 3.466

Review 4.  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

5.  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

6.  Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor.

Authors:  Neil T Burford; Mary J Clark; Tom S Wehrman; Samuel W Gerritz; Martyn Banks; Jonathan O'Connell; John R Traynor; Andrew Alt
Journal:  Proc Natl Acad Sci U S A       Date:  2013-06-10       Impact factor: 11.205

7.  Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties.

Authors:  Thomas M Bridges; Ashley E Brady; J Phillip Kennedy; R Nathan Daniels; Nicole R Miller; Kwango Kim; Micah L Breininger; Patrick R Gentry; John T Brogan; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-09-10       Impact factor: 2.823

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

Authors:  Ya Zhou; Alice L Rodriguez; Richard Williams; C David Weaver; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2009-10-28       Impact factor: 2.823

9.  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

10.  Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas--the effect of capping the distal basic piperidine nitrogen.

Authors:  Nicole R Miller; R Nathan Daniels; Thomas M Bridges; Ashley E Brady; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-09-11       Impact factor: 2.823
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