Journal ArticleDOI
Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.
Allen J. Duplantier,Stacey L. Becker,Michael John Bohanon,Kris A. Borzilleri,Boris A. Chrunyk,James T. Downs,Lain-Yen Hu,Ayman El-Kattan,Larry C. James,Shenping Liu,Jiemin Lu,Noha Maklad,Mahmoud N. Mansour,Scot Richard Mente,Mary Piotrowski,Subas M. Sakya,Sheehan Susan M,Stefanus J. Steyn,Christine A. Strick,Victoria A. Williams,Lei Zhang +20 more
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TLDR
Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.Abstract:
3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.read more
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Carboxylic Acid (Bio)Isosteres in Drug Design
TL;DR: An overview of the most commonly employed carboxylic acid (bio)isosteres is provided and representative examples demonstrating the use and utility of each isostere in drug design are presented.
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The neurobiology of D -amino acid oxidase and its involvement in schizophrenia
TL;DR: This review critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value ofDAO inhibition and highlights issues that have a broader relevance beyond DAO itself.
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The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia.
TL;DR: The complex regulation of endogenous NMDAR D-serine/glycine site agonists is outlined and their contribution to schizophrenia pathogenesis and their potential clinical utility are explored.
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New biotech applications from evolved D-amino acid oxidases
TL;DR: Recent developments in utilizing DAAO are reviewed, including as a biocatalyst for resolving racemic amino acid mixtures, as a tool for biosensing, and as a new mechanism of herbicide resistance.
Journal ArticleDOI
Contributions of the d-serine pathway to schizophrenia
TL;DR: This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor.
References
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Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming.
Daniel K. Gehlhaar,Gennady M. Verkhivker,Paul A. Rejto,Christopher J. Sherman,David B. Fogel,Lawrence J. Fogel,Stephan T. Freer +6 more
TL;DR: This work sets out to develop a strategy for flexible docking by combining a simple model of ligand-protein interactions for molecular recognition with an evolutionary programming search technique, and develops an intermolecular energy function that incorporates steric and hydrogen-bonding terms.
Journal ArticleDOI
Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia.
Kenji Hashimoto,Takeshi Fukushima,Eiji Shimizu,Naoya Komatsu,Hiroyuki Watanabe,Naoyuki Shinoda,Michiko Nakazato,Chikara Kumakiri,Shin-ichi Okada,Hisanori Hasegawa,Kazuhiro Imai,Masaomi Iyo +11 more
TL;DR: Reduced levels of D-serine may play a role in the pathophysiology of schizophrenia, and serum D- and L-Serine levels might provide a measurable biological marker for schizophrenia.
Journal ArticleDOI
In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system.
Bo Feng,Jessica B. Mills,Ralph E. Davidson,Rouchelle J. Mireles,John S. Janiszewski,Matthew D. Troutman,Sonia M. de Morais +6 more
TL;DR: It is demonstrated that in vitro transporter assays help in understanding the role of P-glycoprotein-mediated efflux activity in determining the disposition of CNS drugs in vivo, and the transwell assay is a valuable in vitro assay to evaluate human P-gp interaction with compounds for assessing brain penetration of new chemical entities to treat CNS disorders.