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
  • 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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