Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor

The intricate signaling network within the central nervous system (CNS) involving N-methyl-d-aspartate receptors (NMDARs) has been recognized as a key player in severe neurodegenerative diseases. The indirect modulation of NMDAR-mediated neurotransmission through inhibition of serine racemase (SR)-the enzyme responsible for the synthesis of the NMDAR coagonist D-serine-has been suggested as a therapeutic strategy to treat these conditions. Despite the inherent challenges posed by SR conformational flexibility, a ligand-based drug design strategy has successfully produced a series of potent covalent inhibitors structurally related to amino acid analogues. Among these inhibitors, O-(2-([1,1 '-biphenyl]-4-yl)-1-carboxyethyl)hydroxylammonium chloride (28) has emerged as a valuable candidate with a K-d of about 5 mu M, which makes it one of the most potent hSR inhibitors reported to date. This molecule is expected to inspire the identification of selective hSR inhibitors that might find applications as tools in the study and treatment of several CNS pathologies.