186497-07-4
中文名稱
齊泊騰坦
英文名稱
Zibotentan (ZD4054)
CAS
186497-07-4
分子式
C19H16N6O4S
分子量
424.43
MOL 文件
186497-07-4.mol
更新日期
2024/06/07 17:53:07
186497-07-4 結(jié)構(gòu)式
基本信息
中文別名
賽博特坦齊泊騰坦
化合物ZIBOTENTAN
2-(4-(1,3,4-惡二唑-2-基)苯基)-N-(3-甲氧基-5-甲基吡嗪-2-基)吡啶-3-磺酰胺
N-(3-甲氧基-5-甲基-2-吡嗪基)-2-[4-(1,3,4-惡二唑-2-基)苯基]-3-吡啶磺酰胺
2-(4-(1,3,4-噁二唑-2-基)苯基)-N-(3-甲氧基-5-甲基吡嗪-2-基)吡啶-3-磺酰胺
英文別名
ZD454Zd4054
CS-558
Zd 4054
Zibotentan
Zibotentan(ZD4054)
zibotentan,CID 9910224
ZD4054
ZD-4054
ZD 4054
Zibotentan >=98% (HPLC)
ZIBOTENTAN (ZD4054) 250MG
所屬類別
生物化工：Endothelin Receptor 拮抗劑物理化學(xué)性質(zhì)
熔點(diǎn)239 - 241°C
沸點(diǎn)637.0±65.0 °C(Predicted)
密度1.422
儲(chǔ)存條件Sealed in dry,Store in freezer, under -20°C
溶解度DMSO（少量）、甲醇（少量）
酸度系數(shù)(pKa)5.62±0.40(Predicted)
形態(tài)固體
顏色白色至灰白色
常見問題列表
生物活性
Zibotentan (ZD4054)是一種特異性的Endothelin (ET)A拮抗劑，IC50為21 nM，對(duì)ETB沒有抑制活性。Phase 3。體外研究
As Zibotentan specifically inhibits ETA-mediated antiapoptotic effects, but not ETB-mediated proapoptotic effects in human and rat smooth muscle cells, Zibotentan binds to endothelin A receptor (ETA) with high affinity with Ki of 13 nM, and has no affinity for endothelin B receptor (ETB) with IC50 of >10 μM. Zibotentan treatment at 1 μM inhibits ET-1 induced mitogenic activity in ovarian carcinoma cell lines HEY and OVCA 433 secreting ET-1 and expressing ETA and ETB mRNA. ZD4054 (1 μM) inhibits ET-1 induced EGFR transactivation in HEY and OVCA 433 cells. Zibotentan (1 μM) reverts ET-1 mediated epithelial-mesenchymal transition (EMT), by enhancing E-cadherin expression and promoter activity, and inhibiting vascular endothelial growth factor (VEGF) secretion and invasiveness in HEY and OVCA 433 cells. Zibotentan also potently inhibits the basal and ET-1 induced cell proliferation in SKOV-3 and A-2780 cells, associated with the inhibition of AKT and p42/44MAPK phosphorylation, and with increased apoptosis through the inhibition of bcl-2 and activation of caspase-3 and poly(ADP-ribose) polymerase proteins.體內(nèi)研究
Administration of Zibotentan at 10 mg/kg/day for 21 days potently inhibits the growth of HEY ovarian carcinoma xenografts in mice by 69% with no associated toxicity, which is in association with the blocking of cell proliferation evaluated by 37% inhibition of the Ki-67 expression, and the 62% inhibition of tumor-induced vascularization. Consistently, Zibotentan treatment significantly inhibits the expression of matrix metalloproteinase-2 (MMP-2) and VEGF, as well as the activation of p42/44 MAPK and EGFR, and potently enhances the expression of E-cadherin.靶點(diǎn)
| Target | Value |
| ET-A | 21 nM |
體外研究
在人和大鼠平滑肌細(xì)胞中，Zibotentan特異性抑制ET A 介導(dǎo)的抗凋亡作用，但是對(duì)ET B 介導(dǎo)的促凋亡作用沒有影響，Zibotentan以高親和力結(jié)合于內(nèi)皮素A受體(ET A )，K i 為13 nM，而對(duì)內(nèi)皮素B受體(ETB)沒有親和力，IC50>10 μM。在分泌ET-1，并表達(dá)ET A 與 ET B mRNA的卵巢癌細(xì)胞系HEY和OVCA 433中，1 μM Zibotentan處理抑制ET-1誘導(dǎo)的促有絲分裂活性。 ZD4054 (1 μM)抑制HEY和OVCA 433細(xì)胞中ET-1誘導(dǎo)的EGFR反式激活。HEY和OVCA 433細(xì)胞中，通過(guò)增強(qiáng)E-鈣粘蛋白的表達(dá)和啟動(dòng)子活性，并抑制血管內(nèi)皮生長(zhǎng)因子(VEGF)分泌與侵襲，Zibotentan (1 μM)逆轉(zhuǎn)ET-1介導(dǎo)的上皮-間質(zhì)轉(zhuǎn)化(EMT)。 Zibotentan也能有效抑制SKOV-3和A-2780細(xì)胞中基礎(chǔ)和ET-1誘導(dǎo)的細(xì)胞增殖，這與AKT和p42/44MAPK磷酸化的抑制相關(guān)，也與通過(guò)bcl-2的抑制和caspase-3與聚(ADP-核糖)聚合酶蛋白質(zhì)的激活，導(dǎo)致細(xì)胞凋亡增加相關(guān)。
體內(nèi)研究
Zibotentan(10 mg/kg/day)給藥21天有效抑制小鼠體內(nèi)69%的HEY卵巢癌異種移植物的生長(zhǎng)，而沒有相關(guān)毒性，這與37% Ki-67表達(dá)和62%腫瘤誘導(dǎo)的血管形成被抑制表明的細(xì)胞增殖被阻斷相關(guān)。同樣地，Zibotentan治療顯著抑制基質(zhì)金屬蛋白酶-2 (MMP-2)和VEGF的表達(dá)，以及p42/44 MAPK與EGFR的活化，并有效增強(qiáng)E-鈣粘蛋白的表達(dá)。