The simplest DAO inhibitor benzoic acid was reported in 1956. 4 Since the early 2000s, many small molecule DAO inhibitors have been reported in the literature (Figure ). 5 They all mimic the substrate D-serine and bind to the catalytic site of DAO. The early inhibitors 6 can all be characterized as aryl carboxylic acids or corresponding acid-bioisosteres with low molecular weight. Although they are potent and highly ligand efficient, they lack the vectors that are needed for optimization of potency and physicochemical properties. To that end in 2013, Astellas reported a new class of DAO inhibitors which contain a tail group reaching into a hydrophobic pocket perpendicular to the head group. 7 Takeda also worked on a similar chemical series which culminated in the discovery of their clinical candidate TAK-831 . The kojic acid derivatives were also explored by a Johns Hopkins research group. 8 In addition, Sunovion reported a new class of DAO inhibitors (10) that stabilize an activesite lid-open conformation, although the lead compounds suffer from poor pharmacokinetic and brain penetration properties. 9