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
1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was
further characterized by pKa and isothermal titration calorimetry measurements. Representative
compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA
assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma d-serine level
in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents
a novel class of DAAO inhibitors with the potential to develop drug candidates.
