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.

Journal of medicinal chemistry (2009-05-15)

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 A Piotrowski, Subas M Sakya, Susan Sheehan, Stefanus J Steyn, Christine A Strick, Victoria A Williams, Lei Zhang

PMID19438227

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.

MATERIALS

Product Number

Brand

Product Description

73983

Supelco

Mettler-Toledo Calibration substance ME 18555, Benzoic acid, analytical standard, (for the calibration of the melting point system), traceable to primary standards (LGC)

242381

Sigma-Aldrich

Benzoic acid, ACS reagent, ≥99.5%

12353

Supelco

Benzoic acid, reference material for titrimetry, certified by BAM, >99.5%

33047

Sigma-Aldrich

Benzoic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99.9% (alkalimetric)

18102

Sigma-Aldrich

Benzoic acid, meets analytical specification of Ph. Eur., BP, USP, FCC, E210, 99.5-100.5% (alkalimetric)