Farnesoid X Receptor Agonist for the Treatment of Liver and Metabolic Disorders: Focus on 6-ethyl-CDCA

S.      Fiorucci; S.      Cipriani; A.      Mencarelli; F.      Baldelli; G.      Bifulco; A.      Zampella

doi:10.2174/138955711796355258

Abstract

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 liverrelated 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 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.

Keywords: Chenodeoxycholic acid, FXR, MRP4, non alcoholic liver steatosis (NASH), cholestasis, 6-ethyl-chedeoxycholic acid, 6E-CDCA, farnesoid X, agonistic activity, cholestatic liver diseases, biliary cirrhosis, PBC, NAFLD, NASH, bile sensor, bile acid uptake, metabolism, excretion, atherosclerosis, alkaline phosphatase, Treatment, amelioration, LDL