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. 2023 Jul 12;14(8):1088-1094.
doi: 10.1021/acsmedchemlett.3c00210. eCollection 2023 Aug 10.

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

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

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

Michael T Rudd et al. ACS Med Chem Lett. .

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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Conflict of interest statement

The authors declare the following competing financial interest(s): All authors were employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA at the time of their contribution to this work.

Figures

Figure 1
Figure 1
Screening hit 1 and tool compound 2.
Scheme 1
Scheme 1. General Approach to C4 and C7 Libraries
RC7 amine or heterocycle, DIEA or K2CO3, DMF or CH3CN. Pd(dppf)Cl2, RC7-B(OH)2, K3PO4, dioxane/water, 100 °C. RC4-B(OH)2, Pd(PPh3)4, Na2CO3, dioxane/water, 100 °C. B5—NBS, AIBN, CCl4, then RC7 amine or heterocycle, DIEA or K2CO3, DMF or CH3CN. B6–potassium vinyltrifluoroborate, Pd(OAc)2, RuPhos, Cs2CO3, dioxane, 60 °C. 9-BBN, THF, 60 °C, then Pd2 (dba)3, cataCXium, K2CO3, water.
Figure 2
Figure 2
MK-8768 efficacy in the rhesus ORD task. MK-8768 improved object retrieval in rhesus monkeys following scopolamine impairment. *Indicates significantly different than animals given vehicle prior to scopolamine (white bar).
Scheme 2
Scheme 2. Synthesis of MK-8768
See this image and copyright information in PMC

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