Discovery of isatin and 1H-indazol-3-ol derivatives as d-amino acid oxidase (DAAO) inhibitors

Abstract d -Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d -serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1 H -indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pK a and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1 H -indazol-3-ol ( 37 ) significantly increased plasma d -serine level in an in vivo study on mice. These results show that the 1 H -indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.