Evolution of D-amino acid oxidase inhibitors: From concept to clinic.

Abstract

D-amino acid oxidase (DAAO) is a flavin-dependent peroxisomal monooxygenase with a substrate preference for glycine and certain small hydrophobic D-amino acids. Although the biochemical properties of the enzyme have been extensively studied since 1930s, the therapeutic interest in targeting the enzyme emerged more recently after the physiological significance of endogenous D-serine, a substrate for DAAO, was recognized in 1990s. This triggered a new wave of efforts by many researchers to develop more potent and drug-like DAAO inhibitors with greater translational potential. This chapter recounts the evolution of DAAO inhibitors since then driven by new molecular design strategies guided by structural biology. Some of these inhibitors were investigated in a range of preclinical in vivo studies to assess pharmacokinetics, pharmacodynamics, and behavioral pharmacology. Most importantly, these efforts culminated with the discovery of TAK-831 (luvadaxistat), an orally available brain-penetrant DAAO inhibitor currently under clinical development, representing a true bench-to-bedside success in this field.