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

• Published in: ACS medicinal chemistry letters Vol. 14; no. 8; pp. 1088 - 1094
• Main Authors: Rudd, Michael T., Manley, Peter J., Hanney, Barbara, Meng, Zhaoyang, Shu, Youheng, de Leon, Pablo, Frie, Jessica L., Han, Yongxin, Wai, Jenny Miu-Chun, Yang, Zhi-Qiang, Perkins, James J., Hurzy, Danielle M., Manikowski, Jesse J., Zhu, Hong, Bungard, Christopher J., Converso, Antonella, Meissner, Robert S., Cosden, Mali L., Hayashi, Ikuo, Ma, Lei, O’Brien, Julie, Uebele, Victor N., Schachter, Joel B., Bhandari, Neetesh, Ward, Gwendolyn J., Fillgrove, Kerry L., Lu, Bing, Liang, Yuexia, Dubost, David C., Puri, Vanita, Eddins, Donnie M., Vardigan, Joshua D., Drolet, Robert E., Kern, Jonathan T., Uslaner, Jason M.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.08.2023; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; mGluR2; cognition; Ames; glutamate; OBJECT RETRIEVAL; DESIGN; MEMORY; ENHANCEMENT; CNS; AMPA RECEPTOR; DEFICITS
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00210

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.