Structure-Based Designof Irreversible Human KAT II Inhibitors: Discovery of New Potency-EnhancingInteractions

摘要

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 >4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of kinact/Ki to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.