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

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• 作者：Jamison B. Tuttle ; Marie Anderson ; Bruce M. Bechle ; Brian M. Campbell ; Cheng Chang ; Amy B. Dounay ; Edelweiss Evrard ; Kari R. Fonseca ; Xinmin Gan ; Somraj Ghosh ; Weldon Horner ; Larry C. James ; Ji-Young Kim ; Laura A. McAllister ; Jayvardhan Pandit ; Vinod D. Parikh ; Brian J. Rago ; Michelle A. Salafia ; Christine A. Strick ; Laura E. Zawadzke ; Patrick R. Verhoest
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：4
• 期：1
• 页码：37-40
• 全文大小：344K
• 年卷期：v.4,no.1(January 10, 2013)
• ISSN：1948-5875

文摘

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鈥揳ctivity 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.

Keywords:

kynurenine amino transferase; kynurenic acid; aryl hydrocarbon receptor; irreversible inhibition; hydroxamic acid; dose response modeling; in vivo microdialysis; schizophrenia