Literature DB >> 28947938

Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.

Julie L Engers1,2, Katrina A Bollinger2, Rebecca L Weiner2, Alice L Rodriguez1,2, Madeline F Long2, Megan M Breiner2, Sichen Chang2, Sean R Bollinger2, Michael Bubser1,2, Carrie K Jones1,2,3, Ryan D Morrison2, Thomas M Bridges1,2, Anna L Blobaum1,2, Colleen M Niswender1,2,3, P Jeffrey Conn1,2,3, Kyle A Emmitte1,2, Craig W Lindsley1,2.   

Abstract

Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).

Entities:  

Keywords:  Negative allosteric modulator (NAM); VU6010572; depression; metabotropic glutamate receptor 3 (mGlu3); physiochemical properties

Year:  2017        PMID： 28947938      PMCID： PMC5601378          DOI： 10.1021/acsmedchemlett.7b00249

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  26 in total

1.  Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia.

Authors:  Michael F Egan; Richard E Straub; Terry E Goldberg; Imtiaz Yakub; Joseph H Callicott; Ahmad R Hariri; Venkata S Mattay; Alessandro Bertolino; Thomas M Hyde; Cynthia Shannon-Weickert; Mayada Akil; Jeremy Crook; Radha Krishna Vakkalanka; Rishi Balkissoon; Richard A Gibbs; Joel E Kleinman; Daniel R Weinberger
Journal:  Proc Natl Acad Sci U S A       Date:  2004-08-13       Impact factor: 11.205

Review 2.  mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants.

Authors:  Shigeyuki Chaki; Yukio Ago; Agnieszka Palucha-Paniewiera; Francesco Matrisciano; Andrzej Pilc
Journal:  Neuropharmacology       Date:  2012-05-26       Impact factor: 5.250

3.  Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM.

Authors:  Douglas J Sheffler; Cody J Wenthur; Joshua A Bruner; Sheridan J S Carrington; Paige N Vinson; Kiran K Gogi; Anna L Blobaum; Ryan D Morrison; Mitchell Vamos; Nicholas D P Cosford; Shaun R Stauffer; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2012-04-30       Impact factor: 2.823

Review 4.  Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target.

Authors:  Celia Goeldner; Theresa M Ballard; Frederic Knoflach; Juergen Wichmann; Silvia Gatti; Daniel Umbricht
Journal:  Neuropharmacology       Date:  2012-08-23       Impact factor: 5.250

Review 5.  Metabotropic glutamate receptors: physiology, pharmacology, and disease.

Authors:  Colleen M Niswender; P Jeffrey Conn
Journal:  Annu Rev Pharmacol Toxicol       Date:  2010       Impact factor: 13.820

6.  Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM).

Authors:  Cody J Wenthur; Ryan Morrison; Andrew S Felts; Katrina A Smith; Julie L Engers; Frank W Byers; J Scott Daniels; Kyle A Emmitte; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2013-06-13       Impact factor: 7.446

7.  Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents.

Authors:  Julie L Engers; Alice L Rodriguez; Leah C Konkol; Ryan D Morrison; Analisa D Thompson; Frank W Byers; Anna L Blobaum; Sichen Chang; Daryl F Venable; Matthew T Loch; Colleen M Niswender; J Scott Daniels; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte
Journal:  J Med Chem       Date:  2015-09-10       Impact factor: 7.446

8.  Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function.

Authors:  Hao-Yang Tan; Qiang Chen; Steven Sust; Joshua W Buckholtz; John D Meyers; Michael F Egan; Venkata S Mattay; Andreas Meyer-Lindenberg; Daniel R Weinberger; Joseph H Callicott
Journal:  Proc Natl Acad Sci U S A       Date:  2007-07-16       Impact factor: 11.205

9.  Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).

Authors:  Darren W Engers; Anna L Blobaum; Rocco D Gogliotti; Yiu-Yin Cheung; James M Salovich; Pedro M Garcia-Barrantes; J Scott Daniels; Ryan Morrison; Carrie K Jones; Matthew G Soars; Xiaoliang Zhuo; Jeremy Hurley; John E Macor; Joanne J Bronson; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins
Journal:  ACS Chem Neurosci       Date:  2016-05-03       Impact factor: 4.418

10.  Biological insights from 108 schizophrenia-associated genetic loci.

Authors: 
Journal:  Nature       Date:  2014-07-22       Impact factor: 49.962
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  8 in total

1.  Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress.

Authors:  Max E Joffe; Chiaki I Santiago; Branden J Stansley; James Maksymetz; Rocco G Gogliotti; Julie L Engers; Ferdinando Nicoletti; Craig W Lindsley; P Jeffrey Conn
Journal:  Neuropharmacology       Date:  2018-10-13       Impact factor: 5.250

Review 2.  Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors.

Authors:  Branden J Stansley; P Jeffrey Conn
Journal:  Trends Pharmacol Sci       Date:  2019-02-26       Impact factor: 14.819

3.  mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Authors:  Max E Joffe; Chiaki I Santiago; Kendra H Oliver; James Maksymetz; Nicholas A Harris; Julie L Engers; Craig W Lindsley; Danny G Winder; P Jeffrey Conn
Journal:  Neuron       Date:  2019-11-14       Impact factor: 17.173

4.  The effects of predator odor (TMT) exposure and mGlu3 NAM pretreatment on behavioral and NMDA receptor adaptations in the brain.

Authors:  Ryan E Tyler; Maya N Bluitt; Julie L Engers; Craig W Lindsley; Joyce Besheer
Journal:  Neuropharmacology       Date:  2022-01-07       Impact factor: 5.250

5.  Frontal cortex genetic ablation of metabotropic glutamate receptor subtype 3 (mGlu3) impairs postsynaptic plasticity and modulates affective behaviors.

Authors:  Max E Joffe; Chiaki I Santiago; Sheryl Anne D Vermudez; Nicole M Fisher; Shalini Dogra; Colleen M Niswender; P Jeffrey Conn
Journal:  Neuropsychopharmacology       Date:  2021-05-25       Impact factor: 7.853

6.  Activating mGlu3 Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.

Authors:  Shalini Dogra; Branden J Stansley; Zixiu Xiang; Weilun Qian; Rocco G Gogliotti; Ferdinando Nicoletti; Craig W Lindsley; Colleen M Niswender; Max E Joffe; P Jeffrey Conn
Journal:  Biol Psychiatry       Date:  2021-03-06       Impact factor: 12.810

Review 7.  Recent Advances of Pyridinone in Medicinal Chemistry.

Authors:  Shibo Lin; Chun Liu; Xiaotian Zhao; Xiao Han; Xuanhao Li; Yongqin Ye; Zheyu Li
Journal:  Front Chem       Date:  2022-03-23       Impact factor: 5.221

Review 8.  Targeting metabotropic glutamate receptors for the treatment of depression and other stress-related disorders.

Authors:  Shalini Dogra; P Jeffrey Conn
Journal:  Neuropharmacology       Date:  2021-06-25       Impact factor: 5.273
  8 in total

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