Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B
Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B
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DOI：
10.1021/jm0209026
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发表时间：
2002-09-26
影响因子：
7.3
通讯作者：
Moller, NPH
中科院分区：
文献类型：
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作者：
Andersen, HS;Olsen, OH;Moller, NPH
酪氨酸残基上关键蛋白的可逆磷酸化和去磷酸化是激素和其他因素触发的细胞内信号转导的重要组成部分。最近在小鼠身上进行的基因敲除研究已经确定PTP1B是治疗糖尿病和肥胖症的潜在靶点。因此，许多学术和工业团体都在积极开发选择性PTP1B抑制剂。此外，其他蛋白酪氨酸磷酸酶(PTPs)似乎与癌症和自身免疫等重大疾病密切相关。鉴于PTP的多样性及其在不同疾病中作为药物靶点的潜力，我们采取了广泛的方法来开发这一家族特定成员的活性位点定向选择性抑制剂。通过高通量筛选，我们先前已经确定2-(草酰氨基)苯甲酸3a是几个PTP的相对弱但经典的竞争性抑制剂。(4)在我们早期的研究表明3a可能被用作合成选择性PTP抑制剂的起点的基础上，我们现在介绍了我们在扩展这一概念方面所做的努力，并为开发PTP家族不同成员的抑制剂提供了一些新的化学支架。虽然这些抑制剂的核心结构是带电的，但一些化合物在大鼠体内的口服生物利用度很好。此外，我们观察到前体药物类似物促进了C2C12细胞中2-脱氧葡萄糖的积累。
Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.