Synthesis and Evaluation of 1,3-Disubstituted Imidazolidine-2,4,5-triones as Inhibitors of Pyruvate Carboxylase

被引：1
|
作者：
Schneider, Nicholas O. [1 ]
Gilreath, Kendra [2 ]
Henriksen, Niel M. [3 ]
Donaldson, William A. [2 ]
Chaudhury, Subhabrata [2 ,4 ]
St. Maurice, Martin [1 ]
机构：
[1] Marquette Univ, Dept Chem, Milwaukee, WI 53201 USA
[2] Marquette Univ, Dept Chem, Milwaukee, WI 53201 USA
[3] Atomwise Inc, San Francisco, CA 94108 USA
[4] New York Inst Technol, Coll Art & Sci, Biol & Chem Sci, New York, NY 10023 USA
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2024年
基金：
美国国家卫生研究院;
关键词：
Pyruvate carboxylase; in silico screening; imidazolidinetrione; anaplerosis; INSULIN-SECRETION; GLUCONEOGENESIS; ANAPLEROSIS; SUPPRESSION; SHUTTLE; CELLS;
D O I：
10.1021/acsmedchemlett.4c00183
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Substituted imidazolidinetriones (IZTs) have been identified as potent inhibitors of pyruvate carboxylase (PC) through an in silico screening approach. Alkyl 2-(2,4,5-trioxo-3-substituted imidazolidin-1-yl)acetates (6i-6r) are the most potent of the series, with IC50 values between 3 and 12 mu M, and several IZTs demonstrate high passive permeability across an artificial membrane. IZTs are mixed-type inhibitors with respect to pyruvate and noncompetitive with respect to ATP. This class of inhibitors appears to be selective for PC. Inhibitors in the IZT series do not inhibit the metalloenzymes human carbonic anhydrase II and matrix metalloprotease-12, and they do not inhibit the related biotin-dependent enzyme, guanidine carboxylase. Altogether, IZTs offer promise as PC inhibitors with potential downstream applications in cellular and in vivo systems.
引用
收藏
页码：1088 / 1093
页数：6
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