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

• Published in: ACS medicinal chemistry letters Vol. 4; no. 1; pp. 37 - 40
• Main Authors: Tuttle, Jamison B, Anderson, Marie, Bechle, Bruce M, Campbell, Brian M, Chang, Cheng, Dounay, Amy B, Evrard, Edelweiss, Fonseca, Kari R, Gan, Xinmin, Ghosh, Somraj, Horner, Weldon, James, Larry C, Kim, Ji-Young, McAllister, Laura A, Pandit, Jayvardhan, Parikh, Vinod D, Rago, Brian J, Salafia, Michelle A, Strick, Christine A, Zawadzke, Laura E, Verhoest, Patrick R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.01.2013
• Subjects: Letter; dose response modeling; irreversible inhibition; kynurenine amino transferase; hydroxamic acid; schizophrenia; kynurenic acid; in vivo microdialysis; aryl hydrocarbon receptor
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml300237v

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 k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.