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Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator. | LitMetric

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

ACS Med Chem Lett

Departments of Discovery Chemistry, Neuroscience Biology Discovery, Pharmacology, Nonclinical Dug Safety, Pharmacokinetics, Discovery Pharmaceutical Sciences, and In Vivo Pharmacology, Merck & Co., Inc, West Point, Pennsylvania 19486, United States.

Published: August 2023

AI Article Synopsis

Article Abstract

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424309PMC
http://dx.doi.org/10.1021/acsmedchemlett.3c00210DOI Listing

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