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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- 作者：Allen J. Duplantier ; Stacey L. Becker ; Michael J. 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 ; Mah
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：June 11, 2009
- 年：2009
- 卷：52
- 期：11
- 页码：3576-3585
- 全文大小：280K
- 年卷期：v.52,no.11(June 11, 2009)
- ISSN：1520-4804
文摘
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.