The discovery of fused pyrrole carboxylic acids as novel, potent d-amino acid oxidase (DAO) inhibitors

The ‘NMDA hypofunction hypothesis of schizophrenia’ can be tested in a number of ways. DAO is the enzyme primarily responsible for the metabolism of d-serine, a co-agonist for the NMDA receptor. We identified novel DAO inhibitors, in particular, acid 1, which demonstrated moderate potency for DAO in vitro and ex vivo, and raised plasma d-serine levels after dosing ip to rats. In parallel, analogues were prepared to survey the SARs of 1.

Graphical abstractNovel inhibitors of d-amino acid oxidase (DAO) were discovered. In vivo data for compound 1 showed central and peripheral DAO inhibition and increased peripheral d-serine levels.Figure optionsDownload full-size imageDownload as PowerPoint slide