Most of the known inhibitors of d-amino acid oxidase (DAAO) are small polar molecules
recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors
has been disclosed that interacts with loop 218−224 at the top of the binding pocket.
These compounds have a significantly larger size and more beneficial physicochemical
properties than most reported DAAO inhibitors, however, their structure-activity relationship
is poorly explored. Here we report the synthesis and evaluation of this type of DAAO
inhibitors that open the lid over the active site of DAAO. In order to collect relevant
SAR data we varied two distinct parts of the inhibitors. A systematic variation of
the pendant aromatic substituents according to the Topliss scheme resulted in DAAO
inhibitors with low nanomolar activity. The activity showed low sensitivity to the
substituents investigated. The variation of the linker connecting the pendant aromatic
moiety and the acidic headgroup revealed that the interactions of the linker with
the enzyme were crucial for achieving significant inhibitory activity. Structures
and activities were analyzed based on available X-ray structures of the complexes.
Our findings might support the design of drug-like DAAO inhibitors with advantageous
physicochemical properties and ADME profile.
