Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B)
Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B)
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DOI：
10.1016/s0968-0896(02)00176-1
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发表时间：
2002-10-01
影响因子：
3.5
通讯作者：
James, S
中科院分区：
文献类型：
--
作者：
Liljebris, C;Martinsson, J;James, S
合成了一系列新型哒嗪类似物，并对其作为PTP1B抑制剂的构效关系进行了评价。大多数类似物的效力在低微摩尔范围内。该化合物系列的体外动力学证明它们是可逆的非竞争性结合剂。这表明酶中可能存在另一个位点，通过该位点可以抑制酶活性，该位点不是公认的相互作用结构域。一些类似物对其他PTPases表现出高选择性，例如，化合物12 mp对PTP1B（IC 50 = 5.6 μ M）的选择性是TCPTP和LAR（分别>100 μ M）的20倍。与许多酪氨酸磷酸酶模拟物抑制剂相反，这种化合物类缺乏负电荷，因此显示出跨细胞膜的高渗透性。在体外细胞测定中分析了系列中的选择性类似物，其显示增加的胰岛素刺激的胰岛素受体磷酸化。(C)2002爱思唯尔科技有限公司。保留所有权利。
A series of novel pyridazine analogues were prepared and the structure activity relationship of their behavior as inhibitors of PTP1B was evaluated. Most of the analogues had potencies in the low micromolar range. The in vitro kinetics of this compound series demonstrated that they were reversible non-competitive binders. This indicates that there may exist another site in the enzyme through which enzyme activity can be inhibited, which is not a recognized interaction domain. Some of the analogues exhibited high selectivity for other PTPases, for example, compound 12mp showed 20-fold selectivity for PTP1B (IC50 = 5.6 muM) versus both TCPTP and LAR (>100 muM, respectively). In contrast to many tyrosine phosphatase mimetic inhibitors, this compound class lacks negative charge and thus showed high permeability across cell membranes. Selective analogues in the series were analyzed in an in vitro cellular assay, which showed increased insulin-stimulated insulin receptor phosphorylation. (C) 2002 Elsevier Science Ltd. All rights reserved.