D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids including D-serine, which is a co-agonist of N-methyl-D-aspartate receptor.  We have identified a series of 3-hydroxy-pyridazin-4(1H)-one derivatives as novel DAAO inhibitors using Fragment Based Drug Design.Comparison among complex structures determined in in-house fragment hits and those deposited in PDB, revealed that the hydrophobic sub-pocket was formed perpendicular to the flavin ring by flipping Tyr224 in the compound-dependent manner.  We developed compounds to fill this sub-pocket with the aid of this complex structure information.  Several compounds exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO.  We found that they also had substantial cell permeability and were effective in the MK-801-induced cognitive deficit in the Y-maze.We will report the synthesis, the SAR and the pharmacological properties of 3-hydroxy-pyridazin-4(1H)-one derivatives.

3-Hydroxy-pyridazin-4(1H)-one derivatives as novel D-amino acid oxidase inhibitors

244th National Meeting (2012)

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