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.

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.

MeSH terms

  • Animals
  • Cerebellum / metabolism
  • Crystallography, X-Ray
  • D-Amino-Acid Oxidase / antagonists & inhibitors*
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Humans
  • Hydroxyquinolines / chemical synthesis
  • Hydroxyquinolines / pharmacokinetics*
  • Hydroxyquinolines / pharmacology*
  • Male
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Serine / metabolism
  • Structure-Activity Relationship

Substances

  • Hydroxyquinolines
  • Serine
  • D-Amino-Acid Oxidase

Associated data

  • PDB/3G3E