title: GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improvedin VivoProfile.
abstract: TheN-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.
authors.affiliation: 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.
authors.forename: Elisia
authors.initials: E
authors.lastname: Villemure
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Volgraf
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Cuong Q
authors.initials: CQ
authors.lastname: Ly
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Po-Wai
authors.initials: PW
authors.lastname: Yuen
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Lu
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Luo
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Mingcui
authors.initials: M
authors.lastname: Liu
authors.affiliation: Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lupardus
authors.affiliation: 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.
authors.forename: Heidi J A
authors.initials: HJ
authors.lastname: Wallweber
authors.affiliation: 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.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.affiliation: 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.
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.affiliation: 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.
authors.forename: Emile
authors.initials: E
authors.lastname: Plise
authors.affiliation: 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.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Tay
authors.affiliation: 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.
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Hackos
authors.affiliation: 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.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.affiliation: 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.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Schwarz
authors.affiliation: 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.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sellers
keywords: AMPAR; CNS; EPSP; NMDAR; PAM; allosteric; brain concentration; potentiator; selectivity