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Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.
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Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.

Author: AJ Duplantier Affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. allen.j.duplantier@pfizer.comSL BeckerMJ BohanonKA BorzilleriBA ChrunykAll authors
Edition/Format: Article Article : English
Publication:Journal of medicinal chemistry, 2009 Jun 11; 52(11): 3576-85
Other Databases: WorldCat
Summary:
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  Read more...
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Document Type: Article
All Authors / Contributors: AJ Duplantier Affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. allen.j.duplantier@pfizer.com; SL Becker; MJ Bohanon; KA Borzilleri; BA Chrunyk; JT Downs; LY Hu; A El-Kattan; LC James; S Liu; J Lu; N Maklad; MN Mansour; S Mente; MA Piotrowski; SM Sakya; S Sheehan; SJ Steyn; CA Strick; VA Williams; L Zhang
ISSN:0022-2623
Language Note: English
Unique Identifier: 372761165
Awards:

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.

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