首个非羧酸类FFA4激动剂GSK-137647A的体内药理活性、长期给药有效性及安全性研究

In vivo pharmacological activity,long-term efficacy and safety of GSK-137647A,a first non-carboxylic acid FFA4 agonist

目的阐明首个非羧酸类FFA4激动剂GSK-137647A的体内药理活性、长期给药有效性及安全性,为FFA4激动剂进一步的研究开发奠定基础。方法 a.剂量依赖性试验:雄性ICR小鼠分别给予溶媒,200 mg·kg^(-1)二甲双胍及GSK-137647A(20,40及80 mg·kg^(-1)),给药30 min后灌胃给予3 mg·kg^(-1)葡萄糖,测定葡萄糖耐量(OGTT)。b.低血糖风险评估:空腹ICR小鼠分别给予溶媒,15 mg·kg^(-1)格列本脲及80 mg·kg^(-1) GSK-137647A,测定给药后相应时间点的血糖水平。c.DIO小鼠长期给药研究:雄性C57BL/6小鼠以高脂饲料喂养8周诱导产生DIO模型小鼠,随机分组后连续60天分别灌胃(1天2次,给药间期12 h)给予溶媒,40 mg·kg^(-1) GSK-137647A及200 mg·kg^(-1)二甲双胍,测定第0天和第59天的OGTT,在给药第60天,DIO小鼠摘眼球取血,以生化自动分析仪测定血清生化指标。结果 GSK-137647A体内降糖呈现剂量依赖性,其最大药效剂量约为40 mg·kg^(-1),且低血糖风险较低。在DIO小鼠长期给药实验中,GSK-137647A不会导致FFA4受体脱敏,其介导的外周胰岛素增敏作用使得长期给药后降糖活性显著提高。血清生化分析表明GSK-137647A长期给药后肾功能受损,可能原因在于GSK-137647A的水溶性较差,高剂量长期给药容易在肾脏中形成结晶,对肾脏具有一定的损伤,提示我们通过结构改造以改善其水溶性,将进一步提高其安全性。此外,GSK-137647A可能通过促进GLP-1分泌和改善胰岛素抵抗,发挥降低血糖和血脂的双重药理作用。结论首个非羧酸类FFA4激动剂GSK-137647A具有较好的药理活性及耐受性,具有改善血糖和血脂的双重药理作用,表明FFA4激动剂在改善代谢综合征方面具有广阔应用前景;同时也提出针对GSK-137647A较差的水溶性缺陷进行结构优化的研究思路。

Objective To elucidate the in vivo pharmacological activity,long-term efficacy and safety of GSK-137647 A,the first non-carboxylic acid FFA4 agonist,and lay a foundation for further research and development of FFA4 agonists.Methods a.Dose-dependent test:OGTT was measured in male ICR mice by administration of vehicle,200 mg·kg-1 metformin and GSK-137647 A(20,40 and 80 mg·kg-1),respectively.b.Assessment of hypoglycemia risk:Fasting ICR mice were given vehicle,15 mg·kg-1 glibenclamide and 80 mg·kg-1 GSK-137647 A,respectively.The fasting blood glucose level was measured at the corresponding time points after administration.c.Long-term dosing study in DIO mice:Male C57 BL/6 mice were fed with high-fat diet for 8 weeks to induce DIO model mice with impaired glucose tolerance,which were randomly divided into groups,and administrated vehicle,40 mg·kg-1 GSK-137647 A,and 200 mg·kg-1 metformin on day 0 and day 59 to evaluate the OGTT.On day 60 of administration,DIO mice were bled by eyeball,and the serum biochemical indicators were determined by biochemical analyzer.Results GSK-137647 A showed a significant dose-dependent hypoglycemic effect with a maximum effective dose of 40 mg·kg-1 with a low risk of hypoglycemia.GSK-137647 A did not cause desensitization of FFA4 receptor in long-term administration,and the peripheral insulin sensitization mediated by FFA4 increased the hypoglycemic activity after multiple repeated administrations.Serum biochemical analysis showed that GSK-137647 A slightly impaired renal function after long-term administration,probably due to the poor water solubility of GSK-137647 A,and the high-dose long-term administration resulted in the crystallization of GSK-137647 A in the kidneys,which have some damage to the kidneys.Therefore,the structural optimization of GSK-137647 A to improve the solubility will further enhance its safety.In addition,GSK-137647 A may play a dual pharmacological role in improving blood glucose and lipid by promoting the secretion of GLP-1 and improving insulin resistance.Conclusion GSK-137647 A,the first non-carboxylic acid FFA4 agonist,has good pharmacological activity and tolerability,has double pharmacological effects of improving blood glucose and blood lipid,and validates the broad application prospect of FFA4 agonists in improving metabolic syndrome.At the same time,a design strategy of structural optimization for the improvement of poor water solubility was also proposed.