Literature DB >> 29705142

Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.

Andrew S Felts1, Alice L Rodriguez1, Ryan D Morrison1, Anna L Blobaum1, Frank W Byers1, J Scott Daniels1, Colleen M Niswender2, P Jeffrey Conn1, Craig W Lindsley3, Kyle A Emmitte4.   

Abstract

Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
Copyright © 2018 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Central nervous system (CNS); G protein-coupled receptor (GPCR); Metabotropic glutamate receptor subtype 5 (mGlu(5)); Negative allosteric modulator (NAM); Quinoline

Mesh：

Substances：

Year:  2018        PMID： 29705142      PMCID： PMC6142812          DOI： 10.1016/j.bmcl.2018.04.053

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


  20 in total

Review 1.  Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Authors:  Craig W Lindsley; Kyle A Emmitte; Corey R Hopkins; Thomas M Bridges; Karen J Gregory; Colleen M Niswender; P Jeffrey Conn
Journal:  Chem Rev       Date:  2016-02-16       Impact factor: 60.622

2.  Mavoglurant Augmentation in OCD Patients Resistant to Selective Serotonin Reuptake Inhibitors: A Proof-of-Concept, Randomized, Placebo-Controlled, Phase 2 Study.

Authors:  Daniel Rutrick; Dan J Stein; Ganesan Subramanian; Brian Smith; Maurizio Fava; Gregor Hasler; Jang-Ho Cha; Fabrizio Gasparini; Toni Donchev; Magdalena Ocwieja; Donald Johns; Baltazar Gomez-Mancilla
Journal:  Adv Ther       Date:  2017-01-02       Impact factor: 3.845

Review 3.  Metabotropic Glutamate Receptors in Central Nervous System Diseases.

Authors:  Anna V Golubeva; Rachel D Moloney; Richard M O'Connor; Timothy G Dinan; John F Cryan
Journal:  Curr Drug Targets       Date:  2016       Impact factor: 3.465

4.  The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5.

Authors:  Ryan D Morrison; Anna L Blobaum; Frank W Byers; Tammy S Santomango; Thomas M Bridges; Donald Stec; Katrina A Brewer; Raymundo Sanchez-Ponce; Melany M Corlew; Roger Rush; Andrew S Felts; Jason Manka; Brittney S Bates; Daryl F Venable; Alice L Rodriguez; Carrie K Jones; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte; J Scott Daniels
Journal:  Drug Metab Dispos       Date:  2012-06-18       Impact factor: 3.922

5.  Species-Specific Involvement of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of the Pyrimidine-Containing mGlu5-Negative Allosteric Modulator VU0424238 (Auglurant).

Authors:  Rachel D Crouch; Anna L Blobaum; Andrew S Felts; P Jeffrey Conn; Craig W Lindsley
Journal:  Drug Metab Dispos       Date:  2017-09-22       Impact factor: 3.922

Review 6.  Drug-metabolizing ability of molybdenum hydroxylases.

Authors:  Shigeyuki Kitamura; Kazumi Sugihara; Shigeru Ohta
Journal:  Drug Metab Pharmacokinet       Date:  2006-04       Impact factor: 3.614

7.  Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.

Authors:  Brittney S Bates; Alice L Rodriguez; Andrew S Felts; Ryan D Morrison; Daryl F Venable; Anna L Blobaum; Frank W Byers; Kera P Lawson; J Scott Daniels; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte
Journal:  Bioorg Med Chem Lett       Date:  2014-06-11       Impact factor: 2.823

8.  Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity.

Authors:  Rachel D Crouch; Ryan D Morrison; Frank W Byers; Craig W Lindsley; Kyle A Emmitte; J Scott Daniels
Journal:  Drug Metab Dispos       Date:  2016-03-02       Impact factor: 3.922

9.  Mavoglurant in Parkinson's patients with l-Dopa-induced dyskinesias: Two randomized phase 2 studies.

Authors:  Claudia Trenkwalder; Fabrizio Stocchi; Werner Poewe; Nalina Dronamraju; Chris Kenney; Amy Shah; Florian von Raison; Ana Graf
Journal:  Mov Disord       Date:  2016-05-23       Impact factor: 10.338

10.  Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation.

Authors:  Andrew S Felts; Alice L Rodriguez; Anna L Blobaum; Ryan D Morrison; Brittney S Bates; Analisa Thompson Gray; Jerri M Rook; Mohammed N Tantawy; Frank W Byers; Sichen Chang; Daryl F Venable; Vincent B Luscombe; Gilles D Tamagnan; Colleen M Niswender; J Scott Daniels; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley; Kyle A Emmitte
Journal:  J Med Chem       Date:  2017-05-31       Impact factor: 7.446
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