Literature DB >> 20483612

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

Gábor Wágner1, 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.   

Abstract

Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand efficiency and lipophilic efficiency metrics we identified a promising lead candidate as a starting point for further optimization. Copyright 2010 Elsevier Ltd. All rights reserved.

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Year:  2010        PMID： 20483612     DOI： 10.1016/j.bmcl.2010.04.075

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


  5 in total

1.  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

Review 2.  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

3.  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

Review 4.  Fragile X syndrome: an update on developing treatment modalities.

Authors:  Aileen Healy; Roger Rush; Timothy Ocain
Journal:  ACS Chem Neurosci       Date:  2011-03-22       Impact factor: 4.418

5.  Investigating metabotropic glutamate receptor 5 allosteric modulator cooperativity, affinity, and agonism: enriching structure-function studies and structure-activity relationships.

Authors:  Karen J Gregory; Meredith J Noetzel; Jerri M Rook; Paige N Vinson; Shaun R Stauffer; Alice L Rodriguez; Kyle A Emmitte; Ya Zhou; Aspen C Chun; Andrew S Felts; Brian A Chauder; Craig W Lindsley; Colleen M Niswender; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2012-08-03       Impact factor: 4.436
  5 in total

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