GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile
Year: 2016
Type: article
Abstract: The N -methyl- d -aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca 2+ 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.
Source: ACS Medicinal Chemistry Letters
Authors: 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
Institutions: Genentech, Pharmaron (China)
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: Genentech
OpenAlex ID: W2545250128