title: Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA.
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 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.
authors.affiliation: 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. Fiorucci@unipg.it
authors.forename: S
authors.initials: S
authors.lastname: Fiorucci
authors.forename: S
authors.initials: S
authors.lastname: Cipriani
authors.forename: A
authors.initials: A
authors.lastname: Mencarelli
authors.forename: F
authors.initials: F
authors.lastname: Baldelli
authors.forename: G
authors.initials: G
authors.lastname: Bifulco
authors.forename: A
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008107:Liver Diseases / Q000188:drug therapy*; D008659:Metabolic Diseases / Q000188:drug therapy*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid