Structural, kinetic, and pharmacodynamic mechanisms of d-amino acid oxidase inhibition by small molecules

Seth C. Hopkins, Michele L. R. Heffernan, Lakshmi D. Saraswat, Carrie A. Bowen, Laurence Melnick, Larry W. Hardy, Michael A. Orsini, Michael S. Allen, Patrick Koch, Kerry L. Spear, Robert J. Foglesong, Mustapha Soukri, Milan Chytil, Q. Kevin Fang, Steven W. Jones, Mark A. Varney, Aude Panatier, Stephane H. R. Oliet, Loredano Pollegioni, Luciano Piubelli, Gianluca Molla, Marco Nardini, Thomas H. Large
J. Med. Chem.. 2013-04-30; 56(9): 3710-3724
DOI: 10.1021/jm4002583

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1. J Med Chem. 2013 May 9;56(9):3710-24. doi: 10.1021/jm4002583. Epub 2013 Apr 30.

Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase
inhibition by small molecules.

Hopkins SC(1), Heffernan ML, Saraswat LD, Bowen CA, Melnick L, Hardy LW, Orsini
MA, Allen MS, Koch P, Spear KL, Foglesong RJ, Soukri M, Chytil M, Fang QK, Jones
SW, Varney MA, Panatier A, Oliet SH, Pollegioni L, Piubelli L, Molla G, Nardini
M, Large TH.

Author information:
(1)Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts 01752, United

We characterized the mechanism and pharmacodynamics of five structurally distinct
inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of
human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM).
Stopped-flow experiments showed that pyrrole-based inhibitors possessed high
affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the
presence of substrate, while inhibitors with pendent aromatic groups altered
conformations of the active site lid, as evidenced by X-ray crystallography, and
showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced
a closed-lid conformation, had slower release in the presence of substrate, and
were more potent than benzoate. Steady-state d-serine concentrations were
described in a PK/PD model, and competition for d-serine sites on NMDA receptors
was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence
of glial-derived d-serine, suggesting localized effects on neuronal circuits
where DAAO can exert a neuromodulatory role.

DOI: 10.1021/jm4002583
PMID: 23631755 [Indexed for MEDLINE]

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