1374598-80-7
中文名稱
TAK875
英文名稱
TAK875
CAS
1374598-80-7
分子式
C29H32O7S.1/2H2O
更新日期
2024/10/29 10:09:19
分子量
1067.27
MOL 文件
1374598-80-7.mol
1374598-80-7 結(jié)構(gòu)式
基本信息
中文別名
化合物TAK-875 HEMIHYDRATE(3S)-6-[[2',6'-二甲基-4'-[3-(甲基磺?；?丙氧基][1,1'-聯(lián)苯]-3-基]甲氧基]-2,3-二氫-3-苯并呋喃乙酸半水合物
英文別名
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
所屬類別
生物化工：GPR 激動劑物理化學(xué)性質(zhì)
儲存條件-20°C儲存
溶解度DMSO: 100 mg/mL (187.40 mM);Ethanol: Insoluble
水溶解性水：不溶
InChIKeyOJXYMYYDAVXPIK-IWKNALKQSA-N
CAS 數(shù)據(jù)庫1374598-80-7
常見問題列表
生物活性
TAK-875是一種選擇性GPR40激動劑，EC50為14 nM，比油酸有效400倍。體外研究
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.體內(nèi)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)是一種選擇性GPR40激動劑，在表達(dá)人GPR40的CHO細(xì)胞系中EC50為14 nM，比油酸有效400倍。靶點
| Target | Value |
|
GPR40
(CHO cells expressing human GPR40) | 14 nM(EC50) |
體外研究
TAK-875表現(xiàn)出有效的激動劑活性，并對人GPR40受體表現(xiàn)出高結(jié)合親和力，K i 為38 nM。TAK-875對大鼠GPR40受體表現(xiàn)出較弱的親和力，K i 為140 nM。TAK-875表現(xiàn)出良好的選擇性，其對FFA受體家族的其他成員幾乎沒有激動作用，EC50 >10 μM。 TAK-875治療誘導(dǎo)CHO-hGPR40中細(xì)胞內(nèi)IP的產(chǎn)生濃度依賴性增加，EC50為72 nM，比需要更高配體濃度以激活受體的內(nèi)源性配體的激動劑油酸(EC50為29.9 μM)更有效。在hGPR40缺失的對照組CHO細(xì)胞中，無論是TAK-875或是油酸，都不能誘發(fā)IP應(yīng)答。與Gqα介導(dǎo)的信號通路激活一致，TAK-875增加胰島β細(xì)胞中葡萄糖依賴性胰島素分泌。TAK-875對GPR40/FFA1延長的刺激不會引起胰島β細(xì)胞功能障礙或誘導(dǎo)細(xì)胞凋亡。
體內(nèi)研究
在糖尿病大鼠模型中，TAK-875以0.3-3 mg/kg單劑量口服給藥降低血糖波動，并且口服葡萄糖刺激1小時之前，TAK-875給藥能夠增加口服葡萄糖耐量試驗中的胰島素分泌。在2型糖尿病N-STZ-1.5大鼠體內(nèi)，TAK-875(1-10 mg/kg p.o.)給藥明顯提高葡萄糖耐受性，并增加胰島素分泌。此外，在雄性Zucker 糖尿病肥胖大鼠體內(nèi)，TAK-875 (10 mg/kg, p.o.)顯著增加血漿胰島素水平，并降低空腹高血糖，然而在禁食的正常Sprague-Dawley大鼠體內(nèi)，TAK-875即使在30 mg/kg劑量，也不增強胰島素分泌，且不會引起低血糖。