Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions

A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure–activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate <b>4</b>, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of <i>k</i>_inact/<i>K</i>_i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles