Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor

Tresadern, Gary; Cid, José M.; Macdonald, Gregor; Vega, Javier Martínez; Lucas, Ana I. De; García, Aránzazu; Matesanz, Encarnación; Linares, María Lourdes; Oehlrich, Daniel; Lavreysen, Hilde; Biesmans, Ilse; Trabanco, Andrés A.

doi:10.1016/j.bmcl.2009.11.008

Cited by 75 publications

(59 citation statements)

References 18 publications

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“…Although several novel types of positive allosteric modulators have been discovered (XII-XVI in Table 8) (Zhang et al, 2008b;Duplantier et al, 2009;Brnardic et al, 2010;Cid et al, 2010;D'Alessandro et al, 2010;Tresadern et al, 2010), only few negative allosteric modulators of group II mGlu receptors are known. For two non-amino acid-based classes of group II antagonists Wichmann et al, 1999), it has not been clearly established whether they are competitive or allosteric.…”

Section: Allosteric Modulation Of Family C Gpcrsmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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Section: Allosteric Modulation Of Family C Gpcrsmentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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“…Janssen has discovered an interesting series of imidazopyridines as mGluR2 potentiators based on the bioisosteric replacement of the previously reported pyridone core [119]. The first patent application is the combination of the imidazopyridine core and the previously reported lipophilic side chains at C-7 [120].…”

Section: Imidazopyridinesmentioning

confidence: 99%

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Szabó¹,

Keserü²

2014

CTMC

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This review summarizes drug discovery efforts on mGluR2 positive allosteric modulators IntroductionGlutamate is the major excitatory neurotransmitter that plays a role in eliciting and modulating synaptic responses. These processes involve ionotropic (AMPA, NMDA, kainate) and metabotropic receptors. Up to now eight metabotropic glutamate (mGluR) receptors have been described and characterized [1] and were classified into three subgroups based on their similarity in sequence, signaling and pharmacology [2]. Most of the drug discovery interest has been focused to Group I and Group II targets that include mGluR1/mGluR5 and mGluR2/mGluR3 receptors, respectively. Inhibition of mGluR1 receptors has been connected to anxiolytic [3] and analgesic [4] effects. Negative modulation of mGluR5 receptors found to be beneficial in the animal models of anxiety, depression, Fragile-X and autism spectrum disorder (ASD) [5,6]. mGluR5 positive allosteric modulators (PAMs) are believed to be attractive as a potential pharmacotherapy of schizophrenia [7]. In addition to mGluR5 PAMs compounds targeting Group II receptors are also considered as a promising treatment option for schizophrenia. mGluR2 and mGluR3 receptors impact the glutamatergic transmission in certain brain areas implicated in the pathophysiology of schizophrenia. These neurobiological observations have been validated in the experimental models of schizophrenia indicating that Group II mGluR agonists are effective in a number of antipsychotic animal models [8][9][10][11]. One of the best characterized compounds from this class is the mGluR2/3 receptor agonists LY404039 that showed remarkable efficacy in animal

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“…5,39−46 These compounds invariably resulted from the optimization of hits obtained from high-throughput screening (HTS) of small molecule libraries. PAMs, through their interaction at allosteric sites on the mGlu receptor, positively modulate ( i.e .…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu_2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence

et al. 2014

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As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure–activity relationship (SAR) studies around a series of group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4–8 or 45 other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu2 and PAM activity at mGlu3. The most potent mGlu2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu2/3 PAMs. On the basis of its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu2/3 receptor PAMs have significant potential as small molecule tools for investigating group II mGlu pharmacology.

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Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor

Cited by 75 publications

References 18 publications

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu_2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence

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Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor

Cited by 75 publications

References 18 publications

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence

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Design and Synthesis of Systemically Active Metabotropic Glutamate Subtype-2 and -3 (mGlu_2/3) Receptor Positive Allosteric Modulators (PAMs): Pharmacological Characterization and Assessment in a Rat Model of Cocaine Dependence