Literature DB >> 26778256

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.

Pedro M Garcia-Barrantes1, Hyekyung P Cho2, Adam M Metts3, Anna L Blobaum1, Colleen M Niswender2, P Jeffrey Conn2, Craig W Lindsley4.   

Abstract

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
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： 26778256      PMCID： PMC4794757          DOI： 10.1016/j.bmcl.2015.12.104

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

Review 4.  "Molecular switches" on mGluR allosteric ligands that modulate modes of pharmacology.

Authors:  Michael R Wood; Corey R Hopkins; John T Brogan; P Jeffrey Conn; Craig W Lindsley
Journal:  Biochemistry       Date:  2011-03-04       Impact factor: 3.162

5.  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

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
  9 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.  Re-exploration of the mGlu₁ PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR.

Authors:  Pedro M Garcia-Barrantes; Hyekyung P Cho; Tahj M Starr; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-03-14       Impact factor: 2.823

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

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:  2016-03-10       Impact factor: 2.823

4.  Activation of the mGlu1 metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M4 muscarinic receptor allosteric modulators.

Authors:  Samantha E Yohn; Daniel J Foster; Dan P Covey; Mark S Moehle; Jordan Galbraith; Pedro M Garcia-Barrantes; Hyekyung P Cho; Michael Bubser; Anna L Blobaum; Max E Joffe; Joseph F Cheer; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn
Journal:  Mol Psychiatry       Date:  2018-08-16       Impact factor: 15.992

5.  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 6.  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

7.  mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits.

Authors:  James Maksymetz; Nellie E Byun; Deborah J Luessen; Brianna Li; Robert L Barry; John C Gore; Colleen M Niswender; Craig W Lindsley; Max E Joffe; P Jeffrey Conn
Journal:  Cell Rep       Date:  2021-11-02       Impact factor: 9.423

Review 8.  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

9.  Design and Synthesis of N-phenyl Phthalimides as Potent Protoporphyrinogen Oxidase Inhibitors.

Authors:  Wei Gao; Xiaotian Li; Da Ren; Susu Sun; Jingqian Huo; Yanen Wang; Lai Chen; Jinlin Zhang
Journal:  Molecules       Date:  2019-11-29       Impact factor: 4.411
  9 in total

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