基于异羟肟酸酯的谷氨酸羧肽酶II抑制剂的合成与生物学评价
Synthesis and biological evaluation of hydroxamate-Based inhibitors of glutamate carboxypeptidase II.
作者信息
Stoermer Doris, Liu Qun, Hall Monicia R, Flanary Juliet M, Thomas Ajit G, Rojas Camilo, Slusher Barbara S, Tsukamoto Takashi
机构信息
Guilford Pharmaceuticals Inc., 6611 Tributary Street, MD 21224, Baltimore, USA.
出版信息
Bioorg Med Chem Lett. 2003 Jul 7;13(13):2097-100. doi: 10.1016/s0960-894x(03)00407-4.
A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a P1' residue (primed-side inhibitors) were more potent than those based on a P1 group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC(50) value of 220nM. The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MMP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition.
已经制备了一系列异羟肟酸作为谷氨酸羧肽酶II（GCP II）的潜在抑制剂。基于P1'残基的化合物（引发侧抑制剂）比基于P1基团的化合物（未引发侧抑制剂）更有效。发现引发侧GCP II抑制剂的抑制效力取决于异羟肟酸基团与戊二酸之间亚甲基单元的数量。琥珀酰异羟肟酸衍生物2-（羟基亚氨基甲酰甲基）戊二酸是最有效的GCP II抑制剂，IC（50）值为220nM。将结果与其他类别的GCP II抑制剂以及基于异羟肟酸的基质金属蛋白酶抑制剂的结果进行比较，可进一步深入了解GCP II抑制的构效关系。
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