SCO-267，一种 GPR40 全激动剂，改善糖尿病和肥胖症大鼠模型的血糖和体重控制。
SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity.
机构信息
Takeda Pharmaceutical Company Limited, Kanagawa, Japan (H.U., R.I., H.M., H.O., Y.Mi., T.Y., Y.T., K.T., N.N.); and SCOHIA PHARMA, Inc., Kanagawa, Japan (S.A., M.O., A.K., M.W., Y.Y., T.M., Y.Mo.).
Takeda Pharmaceutical Company Limited, Kanagawa, Japan (H.U., R.I., H.M., H.O., Y.Mi., T.Y., Y.T., K.T., N.N.); and SCOHIA PHARMA, Inc., Kanagawa, Japan (S.A., M.O., A.K., M.W., Y.Y., T.M., Y.Mo.)
出版信息
J Pharmacol Exp Ther. 2019 Aug;370(2):172-181. doi: 10.1124/jpet.118.255885. Epub 2019 Jun 10.
The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout ( ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low--expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.
GPR40/FFA1 受体是一种在胰腺胰岛和肠内分泌细胞中表达的 G 蛋白偶联受体。在这里，我们报告了新型 GPR40 全激动剂（3）-3-环丙基-3-{2-[(1-{2-[(2,2-二甲基丙基)(6-甲基吡啶-2-基)氨基甲酰基]-5-甲氧基苯基}哌啶-4-基)甲氧基]吡啶-4-基}丙酸（SCO-267）的药理学特征。在表达 GPR40 的 CHO、MIN6 和 GLUTag 细胞中评估了 Ca 信号转导和胰岛素及胰高血糖素样肽-1（GLP-1）的分泌。在大鼠中测试了激素分泌和对空腹血糖的影响。在新生链脲佐菌素诱导的糖尿病大鼠（N-STZ-1.5 大鼠）、饮食诱导肥胖（DIO）大鼠和 GPR40 敲除（）小鼠中评估了单次或重复给药的效果。用 SCO-267 处理可激活高表达和低表达的 CHO 细胞中的 Gq 信号，刺激 MIN6 细胞中的胰岛素分泌，并诱导 GLUTag 细胞中 GLP-1 的释放。在正常大鼠中，SCO-267 在非禁食条件下增加胰岛素、胰高血糖素、GLP-1、葡萄糖依赖性胰岛素释放肽和肽 YY（PYY）的分泌。这些结果表明 SCO-267 对 GPR40 具有完全激动剂的特性。在禁食条件下，用 SCO-267 治疗的大鼠不会引起低血糖。在单次和 2 周给药研究中，SCO-267 对糖尿病 N-STZ-1.5 大鼠具有改善葡萄糖耐量的高度有效性。用 SCO-267 治疗 2 周的 DIO 大鼠显示血浆 GLP-1 和 PYY 水平升高，摄食量减少，体重减轻。在野生型小鼠中，SCO-267 诱导 GLP-1 分泌、抑制摄食和减轻体重；然而，这些作用在 小鼠中被消除，表明这是一种 GPR40 依赖性机制。总之，SCO-267 刺激胰岛和肠道激素分泌，改善糖尿病大鼠的血糖控制，并降低肥胖大鼠的体重。这些数据表明 SCO-267 治疗糖尿病和肥胖症的潜在治疗价值。
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