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

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

Affiliation

  • 1 Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. allen.j.duplantier@pfizer.com
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.

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