Literature DB >> 26988302

Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.

Pedro M Garcia-Barrantes1, Hyekyung P Cho2, Anna L Blobaum1, Colleen M Niswender2, P Jeffrey Conn2, Craig W Lindsley3.   

Abstract

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Metabotropic glutamate receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure–activity relationship (SAR); mGlu(1)

Mesh：

Substances：

Year:  2016        PMID： 26988302      PMCID： PMC4823774          DOI： 10.1016/j.bmcl.2016.03.031

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


  9 in total

1.  Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.

Authors:  Carrie K Jones; Darren W Engers; Analisa D Thompson; Julie R Field; Anna L Blobaum; Stacey R Lindsley; Ya Zhou; Rocco D Gogliotti; Satyawan Jadhav; Rocio Zamorano; Jim Bogenpohl; Yoland Smith; Ryan Morrison; J Scott Daniels; C David Weaver; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins
Journal:  J Med Chem       Date:  2011-10-19       Impact factor: 7.446

2.  Development of Novel, CNS Penetrant Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 1 (mGlu1), Based on an N-(3-Chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide Scaffold, That Potentiate Wild Type and Mutant mGlu1 Receptors Found in Schizophrenics.

Authors:  Pedro M Garcia-Barrantes; Hyekyung P Cho; Colleen M Niswender; Frank W Byers; Charles W Locuson; Anna L Blobaum; Zixiu Xiang; Jerri M Rook; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2015-10-08       Impact factor: 7.446

3.  Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core.

Authors:  Pedro M Garcia-Barrantes; Hyekyung P Cho; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2015-10-09       Impact factor: 2.823

4.  Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers.

Authors:  Eric Vieira; Jörg Huwyler; Synèse Jolidon; Frédéric Knoflach; Vincent Mutel; Jürgen Wichmann
Journal:  Bioorg Med Chem Lett       Date:  2009-02-06       Impact factor: 2.823

5.  Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.

Authors:  Pedro M Garcia-Barrantes; Hyekyung P Cho; Adam M Metts; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-01-02       Impact factor: 2.823

6.  Deleterious GRM1 mutations in schizophrenia.

Authors:  Mohammed Akli Ayoub; Dora Angelicheva; David Vile; David Chandler; Bharti Morar; Juleen A Cavanaugh; Peter M Visscher; Assen Jablensky; Kevin D G Pfleger; Luba Kalaydjieva
Journal:  PLoS One       Date:  2012-03-20       Impact factor: 3.240

7.  Chemical modulation of mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenics.

Authors:  Hyekyung P Cho; Pedro M Garcia-Barrantes; John T Brogan; Corey R Hopkins; Colleen M Niswender; Alice L Rodriguez; Daryl F Venable; Ryan D Morrison; Michael Bubser; J Scott Daniels; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Chem Biol       Date:  2014-08-28       Impact factor: 5.100

8.  Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).

Authors:  Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Meredith J Noetzel; Hyekyung P Cho; Atin Lamsal; Emery Smith; Peter Chase; Peter S Hodder; Colleen M Niswender; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley; Michael R Wood
Journal:  J Med Chem       Date:  2014-09-03       Impact factor: 7.446

9.  Clustered coding variants in the glutamate receptor complexes of individuals with schizophrenia and bipolar disorder.

Authors:  René A W Frank; Allan F McRae; Andrew J Pocklington; Louie N van de Lagemaat; Pau Navarro; Mike D R Croning; Noboru H Komiyama; Sophie J Bradley; R A John Challiss; J Douglas Armstrong; Robert D Finn; Mary P Malloy; Alan W MacLean; Sarah E Harris; John M Starr; Sanjeev S Bhaskar; Eleanor K Howard; Sarah E Hunt; Alison J Coffey; Venkatesh Ranganath; Panos Deloukas; Jane Rogers; Walter J Muir; Ian J Deary; Douglas H Blackwood; Peter M Visscher; Seth G N Grant
Journal:  PLoS One       Date:  2011-04-29       Impact factor: 3.240
  9 in total
  4 in total

Review 1.  mGlu1 receptor as a drug target for treatment of substance use disorders: time to gather stones together?

Authors:  Olga A Dravolina; Edwin Zvartau; Wojciech Danysz; Anton Y Bespalov
Journal:  Psychopharmacology (Berl)       Date:  2017-03-11       Impact factor: 4.530

2.  mGlu1-mediated restoration of prefrontal cortex inhibitory signaling reverses social and cognitive deficits in an NMDA hypofunction model in mice.

Authors:  Deborah J Luessen; Isabel M Gallinger; Anthony S Ferranti; Daniel J Foster; Bruce J Melancon; Craig W Lindsley; Colleen M Niswender; Jeffrey Conn
Journal:  Neuropsychopharmacology       Date:  2022-05-28       Impact factor: 8.294

Review 3.  Targeting metabotropic glutamate receptors for novel treatments of schizophrenia.

Authors:  James Maksymetz; Sean P Moran; P Jeffrey Conn
Journal:  Mol Brain       Date:  2017-04-26       Impact factor: 4.041

Review 4.  Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.

Authors:  Deborah J Luessen; P Jeffrey Conn
Journal:  Pharmacol Rev       Date:  2022-07       Impact factor: 18.923
  4 in total

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