Portal de Periódicos da CAPES

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

2009; American Chemical Society; Volume: 52; Issue: 11 Linguagem: Inglês

10.1021/jm900128w

1520-4804

Allen J. Duplantier, Stacey L. Becker, Michael J. Bohanon, Kris A. Borzilleri, Boris A. Chrunyk, James T. Downs, Lain‐Yen Hu, Ayman F. El‐Kattan, Larry C. James, Shenping Liu, Jiemin Lu, Noha Maklad, Mahmoud N. Mansour, Scot Mente, Mary Piotrowski, Subas M. Sakya, Susan Sheehan, Stefanus J. Steyn, Christine A. Strick, Victoria A. Williams, Lei Zhang,

Epigenetics and DNA Methylation

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.