Discovery, SAR, and Pharmacokinetics of a Novel 3-Hydroxyquinolin-2(1H)-one Series of Potentd-Amino Acid Oxidase (DAAO) Inhibitors
Journal of Medicinal Chemistry2009Vol. 52(11), pp. 3576–3585
Citations Over TimeTop 10% of 2009 papers
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, Mahmoud N. Mansour, Scot Mente, Mary 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.
Related Papers
- → Identification and role of ionizing functional groups at the active center of Rhodotorula gracilisD‐amino acid oxidase(2001)17 cited
- → High yielding culture conditions for the biosynthesis of D-amino acid oxidase byTrigonopsis variabilis(1992)15 cited
- → Development of a fluorometric assay for amino-acid oxidase activity and its application to the study of human tissues(1982)11 cited
- → The action of d-amino acid oxidase on ϵ-acyllysine and lysine(1958)4 cited
- → A mini-scale method for assay of D-amino acid oxidase activity inTrigonopsis variabilisagainst cephalosporin C(2005)1 cited