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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >DS-8500a, an Orally Available G Protein-Coupled Receptor 119 Agonist, Upregulates Glucagon-Like Peptide-1 and Enhances Glucose-Dependent Insulin Secretion and Improves Glucose Homeostasis in Type 2 Diabetic Rats
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DS-8500a, an Orally Available G Protein-Coupled Receptor 119 Agonist, Upregulates Glucagon-Like Peptide-1 and Enhances Glucose-Dependent Insulin Secretion and Improves Glucose Homeostasis in Type 2 Diabetic Rats

机译：DS-8500A，口服G蛋白偶联受体119激动剂，上调胰高血糖素肽-1，并增强葡萄糖依赖性胰岛素分泌，并改善2型糖尿病大鼠的葡萄糖稳态

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G protein-coupled receptor 119 (GPR119) has been shown to be highly expressed in small intestinal L-cells and pancreatic beta-cells and mediates intracellular cAMP concentration, glucagon-like peptide (GLP-1) secretion, and glucose-stimulated insulin secretion (GSIS). This study examined the pharmacological effects of 4-(5-{(1R)-1-[4-(cyclopropylcarbonyl) phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(2R)-1-hydroxypropan-2-yl]benzannide (DS-8500a), a novel, orally available, selective GPR119 agonist. In in vitro studies, DS-8500a increased intracellular cAMP in a concentration-dependent manner in human, rat, and mouse GPR119-expressing Chinese hamster ovary (CHO)-K1 cells, with EC50 values of 51.5, 98.4, and 108.1 nmol/l, respectively. DS-8500a had no effect on intracellular cAMP in pcDNA3.1/CHO-K1 cells. In in vivo studies, DS-8500a augmented plasma GLP-1 concentration in Zucker fatty (ZF) rats, and enhanced GSIS and did not change plasma glucose concentration in fasted Sprague-Dawley (SD) rats. A single dose of DS-8500a showed dose-dependent glucose-lowering effects at oral glucose tolerance test (OGTT) in ZF rats. In a repeat-dosing study, DS-8500a had statistically significant glucose-lowering effects at OGTT performed at the 1st day and after 2 weeks of treatment in neonatal streptozotocin-treated (nSTZ) rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982, which had been clinically tested previously as GPR119 agonists. Through pharmacokinetics and pharmacodynamics assessment, the high intrinsic activity of DS-8500a was suggested to be one of the reasons for the greater glucose lowering effect in the nSTZ rats. DS-8500a is a useful compound among GPR119 agonists that can maximize the potential benefit of GPR119 in type 2 diabetes.
机译：G蛋白偶联受体119（GPR119）已被证明在小肠L细胞和胰腺β细胞中高度表达，并介导细胞内CAMP浓度，胰高血糖素样肽（GLP-1）分泌，以及葡萄糖刺激的胰岛素分泌（GSIS）。本研究检测了4-（5 - {（1R）-1- [4-（环丙基羰基）苯氧基]丙基} -1,2,4-恶二唑-3-基）-2-氟-N- [ （2R）-1-羟丙烷-2-基]苯扎尼（DS-8500A），一种新颖的，口服，选择性GPR119激动剂。在体外研究中，DS-8500A以人，大鼠和小鼠GPR119的浓度依赖性方式增加细胞内阵营 - 表达中国仓鼠卵巢（CHO）-K1细胞，EC50值为51.5,98.4和108.1 nmol / L. ， 分别。 DS-8500A对PCDNA3.1 / CHO-K1细胞的细胞内阵营没有影响。在体内研究中，DS-8500A在Zucker脂肪（ZF）大鼠中增加了血浆GLP-1浓度，并增强了GSI，并且在禁食Sprague-Dawley（SD）大鼠中没有改变血浆葡萄糖浓度。单剂量DS-8500A在ZF大鼠口服葡萄糖耐量试验（OGTT）中显示了剂量依赖性葡萄糖降低效果。在重复使用的研究中，DS-8500A在第1天进行的OGTT和在新生儿链脲佐菌素治疗（NSTZ）大鼠的治疗后2周，以及每次DS-8500A的疗效水平在统计上显着的葡萄糖 - 降低效果。测试大于GSK1292263或MBX-2982的测试，其先前已作为GPR119激动剂临床测试。通过药代动力学和药效学评估，DS-8500a的高固有活性被认为是NSTZ大鼠更高葡萄糖降低效果的原因之一。 DS-8500A是GPR119激动剂中的一种有用的化合物，可以最大限度地提高2型糖尿病患者GPR119的潜在益处。

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