生物活性

• 描述Endothelin receptors are G protein-coupled receptors (GPCRs) of the β-group of rhodopsin receptors. It can bind to at least four endothelin ligands, ET_A, ET_B (ET_B1, ET_B2) and ET_C ^[3]. Zibotentan (ZD4054) potently inhibited the binding of ¹²⁵iodine-ET-1 to cloned human ET_A expressed in mouse erythroleukaemic cells, with the pIC50 of 8.27 nM, but had no measurable affinity (pIC50>10 μM) for ET_B ^[4]. Treatment with 1 μM Zibotentan for 24 hours inhibited proliferation of serum-starved HEY, OVCA 433, SKOV-3, and A-2780 cells. And Zibotentan at 1 μM decreased the endogenous ET-1-induced phosphorylation/activation of both kinases (AKT and p42/44MAPK) in HEY cells ^[5]. After oral administration of Zibotentan at a dose of ~3 mg/kg/d for 31days, MBP, SBP and DBP of the rats with hypertension decreased by 5.90 (4.75–7.05) mmHg, 5.91 (4.70–7.11) mmHg and 5.69 (4.26–7.12) mmHg, respectively, and the HR and RR rose by 9.23 (6.21–12.3) bpm and 4.62 (1.89–7.35) br/min, respectively ^[6].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00055471	-	-	Completed	-	-
  NCT00055471	Prostatic Neoplasms ... more >> Metastases, Neoplasm Collapse <<	Phase 2	Completed	-	United States, Ohio ... more >> Research Site Cleveland, Ohio, United States, 44195 United States, Wisconsin Research Site Madison, Wisconsin, United States Collapse <<
  NCT00929162	Patients With Advanced Ovarian... more >> Cancer Sensitive to Platinum-based Chemotherapy Collapse <<	Phase 2	Terminated(Primary objective o... more >>f the trial was not met and so there was no benefit in collecting further information) Collapse <<	-	Germany ... more >> Research Site Berlin, Germany Research Site Dresden, Germany Research Site Dusseldorf, Germany Research Site Essen, Germany Research Site Karlsruhe, Germany Research Site Kassel, Germany Research Site Kiel, Germany Research Site Lich, Germany Research Site Magdeburg, Germany Research Site Marburg, Germany Research Site Munchen, Germany Research Site Rostock, Germany Research Site Wiesbaden, Germany Italy Research Site Milano, MI, Italy Research Site Perugia, PG, Italy Research Site Aviano, PN, Italy Research Site Campobasso, Italy Research Site Modena, Italy Research Site Napoli, Italy Research Site Roma, Italy Collapse <<

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• 参考文献

• [1] Rosanò L, Di Castro V, et al. ZD4054, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma cell proliferation. Exp Biol Med (Maywood). 2006 Jun;231(6):1132-5.

  [2] Morris CD, Rose A, et al. Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. Br J Cancer. 2005 Jun 20;92(12):2148-52.

  [3] Shepard DR, Dreicer R. Zibotentan for the treatment of castrate-resistant prostate cancer. Expert Opin Investig Drugs. 2010 Jul;19(7):899-908

  [4] Morris CD, Rose A, et al. Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. Br J Cancer. 2005 Jun 20;92(12):2148-52

  [5] Rosanò L, Di Castro V, et al. ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo. Mol Cancer Ther. 2007 Jul;6(7):2003-11

  [6] Palmer JC, Tayler HM, et al. Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-β-Induced Hypertension and Maintains Cerebral Perfusion. J Alzheimers Dis. 2020;73(3):1185-1199

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