1374598-80-7
中文名称
TAK875
英文名称
TAK875
CAS
1374598-80-7
分子式
C29H32O7S.1/2H2O
更新日期
2024/04/15 13:34:23
分子量
1067.27
MOL 文件
1374598-80-7.mol
1374598-80-7 结构式
基本信息
中文别名
化合物TAK-875 HEMIHYDRATE(3S)-6-[[2',6'-二甲基-4'-[3-(甲基磺酰基)丙氧基][1,1'-联苯]-3-基]甲氧基]-2,3-二氢-3-苯并呋喃乙酸半水合物
英文别名
CS-1926TAK-875(0.5H2O)
TAK875 hemihydrate
TAK-875 hymihydrate
(3S)-6-[[2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy][1,1'-biphenyl]-3-yl]methoxy]-2,3-dihydro-3-benzofuranacetic acid hydrate (2:1)
[(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphe-nyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate
TAK875 (3S)-6-[[2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy][1,1'-biphenyl]-3-yl]methoxy]-2,3-dihydro-3-benzofuranacetic acid
所属类别
生物化工：GPR 激动剂物理化学性质
储存条件-20°C储存
溶解度DMSO: 100 mg/mL (187.40 mM);Ethanol: Insoluble
水溶解性水：不溶
InChIKeyOJXYMYYDAVXPIK-IWKNALKQSA-N
CAS 数据库1374598-80-7
常见问题列表
生物活性
TAK-875是一种选择性GPR40激动剂，EC50为14 nM，比油酸有效400倍。体外研究
TAK-875 exhibits potent agonist activity and high binding affinity to the human GPR40 receptor with Ki of 38 nM. TAK-875 displays weaker affinity toward the rat GPR40 receptor with Ki of 140 nM. TAK-875 displays excellent selectivity, as TAK-875 has little agonist potency to other members of the FFA receptor family with EC50 of >10 μM. TAK-875 treatment induces a concentration-dependent increase in intracellular IP production in CHO-hGPR40 with EC50 of 72 nM, more potently than that of endogenous ligand agonist oleic acid which requires much higher ligand concentrations to activate the receptor with EC50 of 29.9 μM. Neither TAK-875 nor oleic acid elicits an IP response in control CHO cells devoid of hGPR40. Consistent with the activation of the Gqα-mediated signaling pathway, TAK-875 augments glucose-dependent insulin secretion in pancreatic β cells. Prolonged stimulation of GPR40/FFA1 by TAK-875 does not cause pancreatic β Cell dysfunction or induction of apoptosis.体内研究
In a rat model of diabetes, single oral dosing of TAK-875 at 0.3-3 mg/kg reduces the blood glucose excursion and augments insulin secretion during an oral glucose tolerance test, when TAK-875 is administered 1 hour before an oral glucose challenge. In type 2 diabetic N-STZ-1.5 rats, administration of TAK-875 (1-10 mg/kg p.o.) shows a clear improvement in glucose tolerance and augments insulin secretion. Additionally, TAK-875 (10 mg/kg, p.o.) significantly augments plasma insulin levels and reduces fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhances insulin secretion nor causes hypoglycemia even at 30 mg/kg.特征
More potent at activating hGPR40 than oleic acid生物活性
Fasiglifam (TAK-875)是一种选择性GPR40激动剂，在表达人GPR40的CHO细胞系中EC50为14 nM，比油酸有效400倍。靶点
| Target | Value |
|
GPR40
(CHO cells expressing human GPR40) | 14 nM(EC50) |
体外研究
TAK-875表现出有效的激动剂活性，并对人GPR40受体表现出高结合亲和力，K i 为38 nM。TAK-875对大鼠GPR40受体表现出较弱的亲和力，K i 为140 nM。TAK-875表现出良好的选择性，其对FFA受体家族的其他成员几乎没有激动作用，EC50 >10 μM。 TAK-875治疗诱导CHO-hGPR40中细胞内IP的产生浓度依赖性增加，EC50为72 nM，比需要更高配体浓度以激活受体的内源性配体的激动剂油酸(EC50为29.9 μM)更有效。在hGPR40缺失的对照组CHO细胞中，无论是TAK-875或是油酸，都不能诱发IP应答。与Gqα介导的信号通路激活一致，TAK-875增加胰岛β细胞中葡萄糖依赖性胰岛素分泌。TAK-875对GPR40/FFA1延长的刺激不会引起胰岛β细胞功能障碍或诱导细胞凋亡。
体内研究
在糖尿病大鼠模型中，TAK-875以0.3-3 mg/kg单剂量口服给药降低血糖波动，并且口服葡萄糖刺激1小时之前，TAK-875给药能够增加口服葡萄糖耐量试验中的胰岛素分泌。在2型糖尿病N-STZ-1.5大鼠体内，TAK-875(1-10 mg/kg p.o.)给药明显提高葡萄糖耐受性，并增加胰岛素分泌。此外，在雄性Zucker 糖尿病肥胖大鼠体内，TAK-875 (10 mg/kg, p.o.)显著增加血浆胰岛素水平，并降低空腹高血糖，然而在禁食的正常Sprague-Dawley大鼠体内，TAK-875即使在30 mg/kg剂量，也不增强胰岛素分泌，且不会引起低血糖。