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

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

  • ACS Med Chem Lett. 2016 Oct 31;8(1):84-89. doi: 10.1021/acsmedchemlett.6b00388.
Elisia Villemure 1,  Matthew Volgraf 1,  Yu Jiang 2,  Guosheng Wu 2,  Cuong Q Ly 1,  Po-Wai Yuen 2,  Aijun Lu 2,  Xifeng Luo 2,  Mingcui Liu 2,  Shun Zhang 2,  Patrick J Lupardus 1,  Heidi J A Wallweber 1,  Bianca M Liederer 1,  Gauri Deshmukh 1,  Emile Plise 1,  Suzanne Tay 1,  Tzu-Ming Wang 1,  Jesse E Hanson 1,  David H Hackos 1,  Kimberly Scearce-Levie 1,  Jacob B Schwarz 1,  Benjamin D Sellers 1
Affiliations

Affiliations

  • 1 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.
  • 2 Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
PMID: 28105280 DOI: 10.1021/acsmedchemlett.6b00388
Abstract

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.

Keywords

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

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