title: Farnesoid X receptor: from medicinal chemistry to clinical applications.
abstract: The farnesoid X receptor (FXR) is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps in bile acid uptake, metabolism and excretion. In addition, FXR is an ancillary receptor involved in lipid and glucose homeostasis. Steroidal and non-steroidal FXR ligands are currently available. Both groups have shown limitations in the preclinical studies regarding absorption, metabolism, specificity of target and intrinsic toxicity. FXR ligands endowed with agonistic activity are under development for the treatment of cholestatic liver diseases, including primary biliary cirrhosis and metabolic disorders linked to insulin resistance. Despite the fact that results from preclinical models are encouraging, targeting FXR holds potential for side effects (i.e., impaired cholesterol disposal and cholestasis). Thus, results from FXR gene-ablated mice and mice administered an FXR antagonist support a role for FXR antagonists or modulators (i.e., FXR agonists that selectively activate specific subsets of FXR target genes in a tissue) or co-regulator-specific manner.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università Degli Studi di Perugia, Perugia, Italy. fiorucci@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Elenora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy / Q000378:metabolism; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated