Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors

  • J Med Chem. 2009 Jun 11;52(11):3576-85. doi: 10.1021/jm900128w.
Allen J Duplantier  1 ,  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
Affiliations
  • 1. Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. [email protected]
PMID: 19438227 DOI: 10.1021/jm900128w
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.