Literature DB >> 19197923

Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273.

Darren W Engers1, Alice L Rodriguez, Richard Williams, Alexis S Hammond, Daryl Venable, Oluwatomi Oluwatola, Gary A Sulikowski, P Jeffrey Conn, Craig W Lindsley.   

Abstract

An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago-potentiator ADX-47273. This effort identified key substituents in the 3-position of oxadiazole that engendered either mGluR5 ago-potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9-fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.

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Year:  2009        PMID： 19197923      PMCID： PMC2865690          DOI： 10.1002/cmdc.200800357

Source DB:  PubMed          Journal:  ChemMedChem        ISSN： 1860-7179            Impact factor:   3.466


  37 in total

Review 1.  NMDA receptor hypofunction model of schizophrenia.

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Review 7.  Glutamate receptor expression in schizophrenic brain.

Authors:  J H Meador-Woodruff; D J Healy
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8.  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

9.  A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain.

Authors:  Julie A O'Brien; Wei Lemaire; Marion Wittmann; Marlene A Jacobson; Sookhee N Ha; David D Wisnoski; Craig W Lindsley; Hervé J Schaffhauser; Blake Rowe; Cyrille Sur; Mark E Duggan; Douglas J Pettibone; P Jeffrey Conn; David L Williams
Journal:  J Pharmacol Exp Ther       Date:  2004-01-27       Impact factor: 4.030

10.  ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities.

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Journal:  J Pharmacol Exp Ther       Date:  2008-08-27       Impact factor: 4.030
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  21 in total

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2.  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.

Authors:  Alice L Rodriguez; Mark D Grier; Carrie K Jones; Elizabeth J Herman; Alexander S Kane; Randy L Smith; Richard Williams; Ya Zhou; Joy E Marlo; Emily L Days; Tasha N Blatt; Satyawan Jadhav; Usha N Menon; Paige N Vinson; Jerri M Rook; Shaun R Stauffer; Colleen M Niswender; Craig W Lindsley; C David Weaver; P Jeffrey Conn
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4.  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
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5.  Cyclopropyl-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5.

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6.  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
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8.  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

9.  Identification of Metabotropic Glutamate Receptor Subtype 5 Potentiators Using Virtual High-Throughput Screening.

Authors:  Ralf Mueller; Alice L Rodriguez; Eric S Dawson; Mariusz Butkiewicz; Thuy T Nguyen; Stephen Oleszkiewicz; Annalen Bleckmann; C David Weaver; Craig W Lindsley; P Jeffrey Conn; Jens Meiler
Journal:  ACS Chem Neurosci       Date:  2010-01-28       Impact factor: 4.418

10.  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
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