Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor, JTT-551
Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor, JTT-551
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DOI：
10.1111/j.1463-1326.2009.01162.x
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发表时间：
2010-04-01
影响因子：
5.8
通讯作者：
Matsushita, M.
中科院分区：
文献类型：
--
作者：
Fukuda, S.;Ohta, T.;Matsushita, M.
研究方法：以对硝基苯基磷酸酯为底物，测定PTP 1B抑制活性和抑制模式，并评价JTT-551对其他PTPs的选择性，包括T细胞蛋白酪氨酸磷酸酶（TCPTP）、CD 45蛋白酪氨酸磷酸酶（CD 45）和白细胞共同抗原相关蛋白酪氨酸磷酸酶（LAR）。在L 6大鼠骨骼肌成肌细胞（L 6细胞）中评价JTT-551处理的葡萄糖摄取。在体内研究中，我们研究了JTT-551对肥胖基因突变小鼠和db/db小鼠胰岛素受体（IR）磷酸化和血液生化指标的影响。结果：JTT-551对PTP 1B有抑制作用，Ki值为0.22 μ M，呈混合型抑制模式。TCPTP、CD 45和LAR的Ki值分别为9.3、30或更高和30或更高μ M，JTT-551对其他PTP表现出明显的选择性。此外，JTT-551增加胰岛素刺激的L 6细胞中的葡萄糖摄取。在ob/ob小鼠中单次给予JTT-551增强了肝脏的IR磷酸化并降低了葡萄糖水平。在db/db小鼠中，慢性给药显示出低血糖的效果，而没有加速体重gain.Conclusions：JTT-551，一种新开发的PTP 1B抑制剂，通过增强胰岛素信号传导，改善葡萄糖代谢，可能是有用的2型糖尿病的治疗。
Methods: PTP1B inhibitory activity and the inhibition mode were assayed with p-nitrophenyl phosphate as a substrate, and the selectivity of JTT-551 against other PTPs, including T-cell protein tyrosine phosphatase (TCPTP), CD45 protein tyrosine phosphatase (CD45) and leucocyte common antigen-related protein tyrosine phosphatase (LAR), was evaluated. Glucose uptake with JTT-551 treatment was evaluated in L6 rat skeletal myoblasts (L6 cells). In the in vivo study, we investigated the effects on insulin receptor (IR) phosphorylation and blood chemical parameters with JTT-551 administration in ob/ob mice and db/db mice.Results: JTT-551 showed an inhibitory effect on PTP1B with a Ki value of 0.22 mu M, and a mixed-type inhibition mode. Ki values of TCPTP, CD45 and LAR were 9.3, 30 or higher and 30 or higher mu M, respectively, and JTT-551 exhibited clear selectivity against the other PTPs. Moreover, JTT-551 increased the insulin-stimulated glucose uptake in L6 cells. A single administration of JTT-551 in ob/ob mice enhanced the IR phosphorylation of liver and reduced the glucose level. In db/db mice, chronic administration showed a hypoglycaemic effect without an acceleration of body weight gain.Conclusions: JTT-551, a newly developed PTP1B inhibitor, improves glucose metabolism by enhancement of insulin signalling and could be useful in the treatment of type 2 diabetes mellitus.