Literature DB >> 23718281

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).

Cody J Wenthur1, 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.   

Abstract

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.

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Year:  2013        PMID： 23718281      PMCID： PMC3769689          DOI： 10.1021/jm400439t

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  16 in total

1.  Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.

Authors:  Bruce J Melancon; Corey R Hopkins; Michael R Wood; Kyle A Emmitte; Colleen M Niswender; Arthur Christopoulos; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2012-01-06       Impact factor: 7.446

Review 2.  Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).

Authors:  Shaun R Stauffer
Journal:  ACS Chem Neurosci       Date:  2011-06-27       Impact factor: 4.418

Review 3.  Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.

Authors:  Albert J Robichaud; Darren W Engers; Craig W Lindsley; Corey R Hopkins
Journal:  ACS Chem Neurosci       Date:  2011-06-14       Impact factor: 4.418

Review 4.  Recent progress in the synthesis and characterization of group II metabotropic glutamate receptor allosteric modulators.

Authors:  Douglas J Sheffler; Anthony B Pinkerton; Russell Dahl; Athina Markou; Nicholas D P Cosford
Journal:  ACS Chem Neurosci       Date:  2011-04-12       Impact factor: 4.418

Review 5.  "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

6.  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

7.  Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective.

Authors:  Filippo Caraci; Gemma Molinaro; Giuseppe Battaglia; Maria Laura Giuffrida; Barbara Riozzi; Anna Traficante; Valeria Bruno; Milena Cannella; Sara Merlo; Xushan Wang; Beverly A Heinz; Eric S Nisenbaum; Thomas C Britton; Filippo Drago; Maria Angela Sortino; Agata Copani; Ferdinando Nicoletti
Journal:  Mol Pharmacol       Date:  2010-12-15       Impact factor: 4.436

8.  Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression.

Authors:  Brice Campo; Mikhail Kalinichev; Nathalie Lambeng; M El Yacoubi; Isabelle Royer-Urios; Manfred Schneider; Coline Legrand; Delphine Parron; Francoise Girard; Abdelhak Bessif; Sonia Poli; Jean-Marie Vaugeois; Emmanuel Le Poul; Sylvain Celanire
Journal:  J Neurogenet       Date:  2011-12       Impact factor: 1.250

Review 9.  Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

Authors:  P Jeffrey Conn; Arthur Christopoulos; Craig W Lindsley
Journal:  Nat Rev Drug Discov       Date:  2009-01       Impact factor: 84.694

10.  In vitro pharmacological characterization of novel isoxazolopyridone derivatives as allosteric metabotropic glutamate receptor 7 antagonists.

Authors:  Gentaroh Suzuki; Naohiro Tsukamoto; Hiroshi Fushiki; Aki Kawagishi; Masayuki Nakamura; Hideki Kurihara; Morihiro Mitsuya; Mitsuru Ohkubo; Hisashi Ohta
Journal:  J Pharmacol Exp Ther       Date:  2007-07-03       Impact factor: 4.030
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  30 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.  Metabotropic glutamate receptor 2 inhibits thalamically-driven glutamate and dopamine release in the dorsal striatum.

Authors:  Kari A Johnson; Yolanda Mateo; David M Lovinger
Journal:  Neuropharmacology       Date:  2017-01-31       Impact factor: 5.250

3.  VU0810464, a non-urea G protein-gated inwardly rectifying K+ (Kir 3/GIRK) channel activator, exhibits enhanced selectivity for neuronal Kir 3 channels and reduces stress-induced hyperthermia in mice.

Authors:  Baovi N Vo; Kristopher K Abney; Allison Anderson; Ezequiel Marron Fernandez de Velasco; Michael A Benneyworth; John Scott Daniels; Ryan D Morrison; Corey R Hopkins; Charles David Weaver; Kevin Wickman
Journal:  Br J Pharmacol       Date:  2019-05-30       Impact factor: 8.739

4.  Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation.

Authors:  Adam G Walker; Douglas J Sheffler; Andrew S Lewis; Jonathan W Dickerson; Daniel J Foster; Rebecca K Senter; Mark S Moehle; Xiaohui Lv; Branden J Stansley; Zixiu Xiang; Jerri M Rook; Kyle A Emmitte; Craig W Lindsley; P Jeffrey Conn
Journal:  Neuropsychopharmacology       Date:  2017-06-30       Impact factor: 7.853

Review 5.  Drugs for allosteric sites on receptors.

Authors:  Cody J Wenthur; Patrick R Gentry; Thomas P Mathews; Craig W Lindsley
Journal:  Annu Rev Pharmacol Toxicol       Date:  2013-10-02       Impact factor: 13.820

Review 6.  Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications.

Authors:  Shen Yin; Colleen M Niswender
Journal:  Cell Signal       Date:  2014-05-02       Impact factor: 4.315

7.  Genetically Targeted Optical Control of an Endogenous G Protein-Coupled Receptor.

Authors:  Prashant C Donthamsetti; Johannes Broichhagen; Vojtech Vyklicky; Cherise Stanley; Zhu Fu; Meike Visel; Joshua L Levitz; Jonathan A Javitch; Dirk Trauner; Ehud Y Isacoff
Journal:  J Am Chem Soc       Date:  2019-07-10       Impact factor: 15.419

8.  Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction.

Authors:  Adam G Walker; Cody J Wenthur; Zixiu Xiang; Jerri M Rook; Kyle A Emmitte; Colleen M Niswender; Craig W Lindsley; P Jeffrey Conn
Journal:  Proc Natl Acad Sci U S A       Date:  2015-01-12       Impact factor: 11.205

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

Authors:  Julie L Engers; Katrina A Bollinger; Rebecca L Weiner; Alice L Rodriguez; Madeline F Long; Megan M Breiner; Sichen Chang; Sean R Bollinger; Michael Bubser; Carrie K Jones; Ryan D Morrison; Thomas M Bridges; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2017-08-15       Impact factor: 4.345

10.  Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

Authors:  Katrina A Bollinger; Andrew S Felts; Christopher J Brassard; Julie L Engers; Alice L Rodriguez; Rebecca L Weiner; Hyekyung P Cho; Sichen Chang; Michael Bubser; Carrie K Jones; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2017-08-03       Impact factor: 4.345
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