Literature DB >> 21315585

Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold.

Richard Williams1, Jason T Manka, Alice L Rodriguez, Paige N Vinson, Colleen M Niswender, C David Weaver, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley, Shaun R Stauffer.   

Abstract

This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu(5) receptor. 'Molecular switches' were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after ip dosing, a preclinical model that shows similar positive effects with known antipsychotic agents. Published by Elsevier Ltd.

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Year:  2011        PMID： 21315585      PMCID： PMC3498823          DOI： 10.1016/j.bmcl.2011.01.044

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


  20 in total

Review 1.  Treatment of schizophrenia and spectrum disorders: pharmacotherapy, psychosocial treatments, and neurotransmitter interactions.

Authors:  H Y Meltzer
Journal:  Biol Psychiatry       Date:  1999-11-15       Impact factor: 13.382

Review 2.  Discovery of positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5).

Authors:  David L Williams; Craig W Lindsley
Journal:  Curr Top Med Chem       Date:  2005       Impact factor: 3.295

3.  Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold.

Authors:  Sameer Sharma; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-05-29       Impact factor: 2.823

4.  A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models.

Authors:  Gene G Kinney; Julie A O'Brien; Wei Lemaire; Maryann Burno; Denise J Bickel; Michelle K Clements; Tsing-Bau Chen; David D Wisnoski; Craig W Lindsley; Philip R Tiller; Sheri Smith; Marlene A Jacobson; Cyrille Sur; Mark E Duggan; Douglas J Pettibone; P Jeffrey Conn; David L Williams
Journal:  J Pharmacol Exp Ther       Date:  2004-12-17       Impact factor: 4.030

5.  Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo.

Authors:  Craig W Lindsley; David D Wisnoski; William H Leister; Julie A O'brien; Wei Lemaire; David L Williams; Maryann Burno; Cyrille Sur; Gene G Kinney; Doug J Pettibone; Philip R Tiller; Sheri Smith; Mark E Duggan; George D Hartman; P Jeffrey Conn; Joel R Huff
Journal:  J Med Chem       Date:  2004-11-18       Impact factor: 7.446

6.  4-aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators.

Authors:  Hui Xiong; Todd A Brugel; Michael Balestra; Dean G Brown; Kelly A Brush; Caprice Hightower; Lindsay Hinkley; Valerie Hoesch; James Kang; Gerard M Koether; John P McCauley; Francis M McLaren; Laura M Panko; Thomas R Simpson; Reed W Smith; James M Woods; Becky Brockel; Vijay Chhajlani; Reto A Gadient; Nathan Spear; Linda A Sygowski; Minli Zhang; Jalaj Arora; Nathalie Breysse; Julie M Wilson; Methvin Isaac; Abdelmalik Slassi; Megan M King
Journal:  Bioorg Med Chem Lett       Date:  2010-10-21       Impact factor: 2.823

7.  Discovery of a Novel Chemical Class of mGlu(5) Allosteric Ligands with Distinct Modes of Pharmacology.

Authors:  Alexis S Hammond; Alice L Rodriguez; Steven D Townsend; Colleen M Niswender; Karen J Gregory; Craig W Lindsley; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2010-08-19       Impact factor: 4.418

8.  Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines.

Authors:  Sameer Sharma; Jeffrey Kedrowski; Jerri M Rook; Randy L Smith; Carrie K Jones; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2009-07-23       Impact factor: 7.446

9.  A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5.

Authors:  Julie A O'Brien; Wei Lemaire; Tsing-Bau Chen; Raymond S L Chang; Marlene A Jacobson; Sookhee N Ha; Craig W Lindsley; Hervé J Schaffhauser; Cyrille Sur; Douglas J Pettibone; P Jeffrey Conn; David L Williams
Journal:  Mol Pharmacol       Date:  2003-09       Impact factor: 4.436

Review 10.  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
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  15 in total

1.  Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function.

Authors:  Meredith J Noetzel; Jerri M Rook; Paige N Vinson; Hyekyung P Cho; Emily Days; Y Zhou; Alice L Rodriguez; Hilde Lavreysen; Shaun R Stauffer; Colleen M Niswender; Zixiu Xiang; J Scott Daniels; Carrie K Jones; Craig W Lindsley; C David Weaver; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2011-10-21       Impact factor: 4.436

2.  Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.

Authors:  Susana Conde-Ceide; Carlos M Martínez-Viturro; Jesús Alcázar; Pedro M Garcia-Barrantes; Hilde Lavreysen; Claire Mackie; Paige N Vinson; Jerri M Rook; Thomas M Bridges; J Scott Daniels; Anton Megens; Xavier Langlois; Wilhelmus H Drinkenburg; Abdellah Ahnaou; Colleen M Niswender; Carrie K Jones; Gregor J Macdonald; Thomas Steckler; P Jeffrey Conn; Shaun R Stauffer; José Manuel Bartolomé-Nebreda; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2015-05-20       Impact factor: 4.345

3.  Phthalimido-thiazole as privileged scaffold: activity against immature and adult worms of Schistosoma mansoni.

Authors:  Sheilla Andrade de Oliveira; Miria de Oliveira Barbosa; Carlos André Laranjeira Miranda Filho; Arsênio Rodrigues Oliveira; Fabiano Amaro de Sousa; Edna de Farias Santiago; Gevanio Bezerra de Oliveira Filho; Paulo André Teixeira de Moraes Gomes; Juliana Maria da Conceição; Fábio André Brayner; Luiz Carlos Alves; Ana Cristina Lima Leite
Journal:  Parasitol Res       Date:  2018-05-07       Impact factor: 2.289

4.  Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats.

Authors:  V D'Amore; I Santolini; R Celli; L Lionetto; A De Fusco; M Simmaco; C M van Rijn; E Vieira; S R Stauffer; P J Conn; P Bosco; F Nicoletti; G van Luijtelaar; R T Ngomba
Journal:  Neuropharmacology       Date:  2014-05-20       Impact factor: 5.250

5.  Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.

Authors:  Jerri M Rook; Meredith J Noetzel; Wendy A Pouliot; Thomas M Bridges; Paige N Vinson; Hyekyung P Cho; Ya Zhou; Rocco D Gogliotti; Jason T Manka; Karen J Gregory; Shaun R Stauffer; F Edward Dudek; Zixiu Xiang; Colleen M Niswender; J Scott Daniels; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn
Journal:  Biol Psychiatry       Date:  2012-11-07       Impact factor: 13.382

Review 6.  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

7.  Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles.

Authors:  Jerri M Rook; Mohammed N Tantawy; Mohammad S Ansari; Andrew S Felts; Shaun R Stauffer; Kyle A Emmitte; Robert M Kessler; Colleen M Niswender; J Scott Daniels; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn
Journal:  Neuropsychopharmacology       Date:  2014-09-22       Impact factor: 7.853

8.  Drug Design Strategies for GPCR Allosteric Modulators.

Authors:  P Jeffrey Conn; Scott D Kuduk; Darío Doller
Journal:  Annu Rep Med Chem       Date:  2012       Impact factor: 1.059

9.  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 10.  Metabotropic glutamate receptors as therapeutic targets for schizophrenia.

Authors:  Paige N Vinson; P Jeffrey Conn
Journal:  Neuropharmacology       Date:  2011-05-19       Impact factor: 5.250
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