TM5275 sodium (TM5275 sodium salt) is an inhibitor of plasminogen activator inhibitor 1 (PAI-1).

TM5275通过抑制体外血管内皮细胞(VECs)上由组织型纤溶酶原激活剂(tPA)、PAI-1和GFP组成的复合物的形成，延长tPA在VECs上的保留时间。它还能增强体外纤维蛋白凝块的溶解和纤溶酶原的积累，并在大鼠血栓模型中显示出抗血栓效应。对接研究显示，TM5275与PAI-1的Aβ-折叠第4条链(s4A)位置结合。TM5275是一种选择性的PAI-1抑制剂，在高达100μM的浓度下不干涉其他serpin/丝氨酸蛋白酶系统。20和100μM的TM5275显著延长tPA-GFP在VECs上的停留时间，通过抑制tPA-GFP-PAI-1高分子量复合物的形成。TM5275增强了tPA-GFP表达细胞周围纤溶酶原的时间依赖性积累以及纤维蛋白凝块的溶解。在72小时处理后，用70-100μM TM5275对ES-2和JHOC-9细胞的细胞活性降低。从48小时到96小时，用100μM TM5275抑制细胞生长。与对照处理相比，用100μM TM5275处理的细胞培养基中的活性PAI-1显著减少。TM5275被认为在高PAI-1表达的卵巢癌中具有抗增殖效应。

TM5275（10 mg/kg和50 mg/kg）在动静脉分流血栓模型中降低了血栓质量，并在使用1 mg/kg和3 mg/kg剂量时，在铁氯化物处理的颈动脉血栓模型中延长了至主要闭塞的时间。在光化学诱导的动脉血栓病猕猴模型中，TM5275（10 mg/kg）同样延长了至主要闭塞的时间。它不影响血小板活性、激活的部分凝血活酶时间、凝血酶原时间或延长出血时间。TM5275展现了良好的药代动力学特性和对小鼠及大鼠的极低毒性。在大鼠血栓模型中，与对照组处理的大鼠（72.5±2.0 mg）相比，服用TM5275的大鼠（10 mg/kg和50 mg/kg）的血栓质量显著降低（分别为60.9±3.0 mg和56.8±2.8 mg）。TM5275（50 mg/kg）的抗血栓效果与参考抗血栓化合物替格瑞洛（500 mg/kg）相当。TM5275的血浆浓度在10 mg/kg剂量后达到17.5±5.2μM。TM5275（5 mg/kg）与tPA（0.3 mg/kg）联用，显著增强了单独tPA（0.3 mg/kg）的抗血栓效果。

TM5275 exhibits a favorable pharmacokinetics profile and very low toxicity to mice and rats. In rat thrombosis models. Blood clot weights are significantly lower in rats administered 10 and 50?mg/kg of TM5275 (60.9±3.0 and 56.8±2.8?mg, respectively) than in vehicle-treated rats (72.5±2.0?mg). The antithrombotic effectiveness of TM5275 (50?mg/kg) is equivalent to that of ticlopidine (500?mg/kg), a reference antithrombotic compound. Plasma concentration of TM5275 reaches 17.5±5.2?μM after a dose of 10?mg/kg. TM5275 (5?mg/kg) combined with tPA (0.3?mg/kg) significantly enhances the antithrombotic effect of tPA (0.3?mg/kg) alone and provides a benefit similar to that of a high tPA dose (3?mg/kg).

TM5275 is prepared in DMSO.ES2 cells are treated with DMSO (control) or 100 μM TM5275 for the indicated periods (24, 48, 72, 96 hour). Cell growth is determined by CellTiter-Glo assay.

TM5275 is suspended in 0.5% carboxymethyl cellulose sodium salt (CMC).Rats: Thrombus formation in arteriovenous shunts is achieved in male CD rats. Either TM5275 (10 and 50?mg/kg, n=9) or ticlopidine (500?mg/kg, n=6), suspended in 0.5% CMC solution, is administered orally by gavage 90?mins before the study. Control rats are administered only a 0.5% CMC solution (n=10). Blood is allowed to circulate through the shunt for 30?mins. The wet weight of the thrombus covering the silk thread is eventually measured.Mice: TM5275 is administered orally by gavage to male ICR mice (50?mg/kg). Heparinized blood samples are collected from the vein before (0?h) and 1, 2, 6, and 24?h after oral drug administration. Plasma drug concentration is determined on a reverse-phase high-performance liquid chromatography