D-Serine is an endogenous co-agonist at the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor. D-Serine degradation is catalyzed by the flavoenzyme D-amino acid oxidase (DAAO) producing the corresponding imino acid, along with ammonia and hydrogen peroxide as by-products. Oral administration of D-serine in combination with a DAAO inhibitor could improve D-serine pharmacokinetics and provide a new therapeutic option for the treatment of disorders associated with NMDA receptor hypofunction such as schizophrenia. As part of our continuous efforts to identify a new structural class of DAAO inhibitors, a series of kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) derivatives were synthesized and evaluated for their ability to inhibit DAAO. Various substituents were incorporated into kojic acid at its 2-hydroxymethyl group. These analogs serve as useful molecular probes to explore the newly recognized secondary binding site, which can be further exploited in designing more potent DAAO inhibitors. Figure 1. <img src='https://acs-archive-assets2.s3.amazonaws.com/239nm/uploads/9794_tio2.jpg' alt='' />

Synthesis of kojic acid derivatives as secondary binding site probes of D-amino acid oxidase

246th National Meeting (2013)

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