University of Perugia, Dipartimento di Medicina Clinica e Sperimentale, Nuova Facoltà di Medicina e Chirurgia, Via Gerardo Dottori n° 1 S. Andrea delle Fratte, 06132 Perugia, Italy.
Mini Rev Med Chem. 2011 Aug;11(9):753-62. doi: 10.2174/138955711796355258.
6-ethyl-chedeoxycholic acid (6E-CDCA) is a farnesoid X receptor (FXR) ligand endowed with agonistic activity under development for treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) and liver-related metabolic disorders including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). FXR is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps of bile acid uptake, metabolism and excretion. 6E-CDCA has been investigated in preclinical models of cholestasis, liver fibrosis and diet-induced atherosclerosis. In a phase II clinical trial in patients with PBC, 6E-CDCA met the primary endpoint of a reduction in alkaline phosphatase levels but safety data indicated that the drug exacerbated pruritus, one of the main symptoms of PBC, suggesting that 6E-CDCA or FXR are mediators of pruritus in humans. Treatment of patients with diabetes and liver steatosis resulted in amelioration of insulin sensitivity despite a reduction a slight reduction in HDL and increased levels of LDL were observed. These side effects on bile acids and lipid metabolism were all predicted by pre-clinical studies, suggesting that potent FXR ligands hold promise but potential side effects might limit their development.
6-乙基鹅去氧胆酸（6E-CDCA）是一种法尼醇 X 受体（FXR）配体，具有激动活性，目前正在开发用于治疗胆汁淤积性肝病，包括原发性胆汁性肝硬化（PBC）和与肝脏相关的代谢紊乱，包括非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）。FXR 是一种胆汁传感器，与其他核受体协同作用，调节胆汁酸摄取、代谢和排泄的基本步骤。6E-CDCA 已在胆汁淤积、肝纤维化和饮食诱导的动脉粥样硬化的临床前模型中进行了研究。在一项 PBC 患者的 II 期临床试验中，6E-CDCA 达到了降低碱性磷酸酶水平的主要终点，但安全性数据表明该药物加剧了瘙痒，这是 PBC 的主要症状之一，这表明 6E-CDCA 或 FXR 是人类瘙痒的介导物。尽管观察到 HDL 略有下降，LDL 水平升高，但治疗糖尿病和肝脏脂肪变性的患者改善了胰岛素敏感性。这些对胆汁酸和脂质代谢的副作用都被临床前研究所预测，这表明强效的 FXR 配体具有很大的希望，但潜在的副作用可能会限制它们的发展。
