Discovery, SAR, and Pharmacokinetics of a Novel 3-Hydroxyquinolin-2 (1 H)-one Series of Potent d-Amino Acid Oxidase (DAAO) Inhibitors†

…, LY Hu, A El-Kattan, LC James, S Liu, J Lu…

文献索引：Duplantier, Allen J.; Becker, Stacey L.; Bohanon, Michael J.; Borzilleri, Kris A.; Chrunyk, Boris A.; Downs, James T.; Hu, Lain-Yen; El-Kattan, Ayman; James, Larry C.; Liu, Shenping; Lu, Jiemin; Maklad, Noha; Mansour, Mahmoud N.; Mente, Scot; Piotrowski, Mary A.; Sakya, Subas M.; Sheehan, Susan; Steyn, Stefanus J.; Strick, Christine A.; Williams, Victoria A.; Zhang, Lei Journal of Medicinal Chemistry, 2009 , vol. 52, # 11 p. 3576 - 3585

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被引用次数: 67

摘要

3-Hydroxyquinolin-2 (1 H)-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 ...