GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile

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• 作者：Elisia Villemure ; Matthew Volgraf ; Yu Jiang ; Guosheng Wu ; Cuong Q. Ly ; Po-wai Yuen ; Aijun Lu ; Xifeng Luo ; Mingcui Liu ; Shun Zhang ; Patrick J. Lupardus ; Heidi J. A. Wallweber ; Bianca M. Liederer ; Gauri Deshmukh ; Emile Plise ; Suzanne Tay ; Tzu-Ming Wang ; Jesse E. Hanson ; David H. Hackos ; Kimberly Scearce-Levie ; Jacob B. Schwarz ; Benjamin D. Sellers
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：84-89
• 全文大小：401K
• ISSN：1948-5875

文摘

The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca²⁺ and Na⁺. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer’s disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure–activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (13), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences.