2. Academic Validation
  3. Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator

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

  • ACS Med Chem Lett. 2023 Jul 12;14(8):1088-1094. doi: 10.1021/acsmedchemlett.3c00210.
Michael T Rudd 1,  Peter J Manley 1,  Barbara Hanney 1,  Zhaoyang Meng 1,  Youheng Shu 1,  Pablo de Leon 1,  Jessica L Frie 1,  Yongxin Han 2,  Jenny Miu-Chun Wai 1,  Zhi-Qiang Yang 1,  James J Perkins 1,  Danielle M Hurzy 1,  Jesse J Manikowski 1,  Hong Zhu 1,  Christopher J Bungard 1,  Antonella Converso 1,  Robert S Meissner 1,  Mali L Cosden 1,  Ikuo Hayashi 1,  Lei Ma 1,  Julie O'Brien 1,  Victor N Uebele 1,  Joel B Schachter 1,  Neetesh Bhandari 1,  Gwendolyn J Ward 1,  Kerry L Fillgrove 1,  Bing Lu 1,  Yuexia Liang 1,  David C Dubost 1,  Vanita Puri 1,  Donnie M Eddins 1,  Joshua D Vardigan 1,  Robert E Drolet 1,  Jonathan T Kern 1,  Jason M Uslaner 1
Affiliations

Affiliations

  • 1 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.
  • 2 External Discovery Chemistry, Merck & Co., Inc, Boston, Massachusetts 02115, United States.
PMID: 37583812 DOI: 10.1021/acsmedchemlett.3c00210
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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