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
  • 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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