Synthesis and Biological Evaluation of d-Amino Acid Oxidase Inhibitors

d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a full agonist at the glycine site of the NMDA receptor. A series of benzo[d]isoxazol-3-ol derivatives were synthesized and evaluated as DAAO inhibitors. Among them, 5-chloro-benzo[d]isoxazol-3-ol (CBIO) potently inhibited DAAO with an IC₅₀ in the submicromolar range. Oral administration of CBIO in conjunction with d-serine enhanced the plasma and brain levels of d-serine in rats compared to the oral administration of d-serine alone.