Synthesis of D-amino acid oxidase inhibitors and their effects on the plasma and brain levels of D-serine

MEDI 287

Bridget Duvall, bridget.duvall@mgipharma.com1, Dana Ferraris1, Yao-sen Ko1, Ajit Thomas1, Pavel Majer1, Camilo Rojas1, Takashi Tsukamoto1, and Kenji Hashimoto2. (1) Department of Research, MGI Pharma, Inc, 6411 Beckley Street, Baltimore, MD 21224, (2) Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-9-1 Inohana, Chiba, Japan
The preclinical and clinical evidence supporting the role of NMDA receptor hypofunction in schizophrenia has prompted clinical trials of agents that enhance NMDA receptor function. For example, schizophrenic patients receiving D-serine, a full agonist at the glycine site of the NMDA receptor, with concomitant neuroleptic therapy have shown significant improvements in their positive, negative, and cognitive symptoms. In humans, however, D-serine is believed to be metabolized substantially by D-amino acid oxidase (DAAO), diminishing its bioavailability. To address this issue, we have designed small molecule DAAO inhibitors which can be co-administered with D-serine to minimize its metabolism by DAAO. Through our SAR studies, we found that small molecules based on a benzo[d]isoxazol-3-ol core structure potently inhibit DAAO. The most potent compound was tested for its ability to enhance the plasma and brain levels of co-administered D-serine in rats.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007