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ACS Med Chem Lett. 2016 Oct 31;8(1):84-89. doi: 10.1021/acsmedchemlett.6b00388. eCollection 2017 Jan 12.

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

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Department of Discovery Chemistry, Department of Neurosciences, Department of Biochemical and Cellular Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.


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.


AMPAR; CNS; EPSP; NMDAR; PAM; allosteric; brain concentration; potentiator; selectivity

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