| Literature DB >> 19438227 |
Allen J Duplantier1, 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, Mahmoud N Mansour, Scot Mente, Mary A Piotrowski, Subas M Sakya, Susan Sheehan, Stefanus J Steyn, Christine A Strick, Victoria A Williams, Lei Zhang.
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.Entities:
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Year: 2009 PMID： 19438227 DOI： 10.1021/jm900128w
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446