Abstract
The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/ activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocytes basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding sideeffects linked to FXR activation.
Keywords: Bile acids, cholestasis, constitute-androstane-receptor, farnesoid-x-receptor, hepatocytes, pregnane-x-receptor, constitute-androstane-receptor (CAR), bile acids secretion, hepatocyte's basolateral transporters, obstructivecholestasis, antagonists, liver disorders
Current Topics in Medicinal Chemistry
Title: Development of FXR, PXR and CAR Agonists and Antagonists for Treatment of Liver Disorders
Volume: 12 Issue: 6
Author(s): Stefano Fiorucci, Angela Zampella and Eleonora Distrutti
Affiliation:
Keywords: Bile acids, cholestasis, constitute-androstane-receptor, farnesoid-x-receptor, hepatocytes, pregnane-x-receptor, constitute-androstane-receptor (CAR), bile acids secretion, hepatocyte's basolateral transporters, obstructivecholestasis, antagonists, liver disorders
Abstract: The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/ activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocytes basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding sideeffects linked to FXR activation.
Export Options
About this article
Cite this article as:
Fiorucci Stefano, Zampella Angela and Distrutti Eleonora, Development of FXR, PXR and CAR Agonists and Antagonists for Treatment of Liver Disorders, Current Topics in Medicinal Chemistry 2012; 12 (6) . https://dx.doi.org/10.2174/156802612799436678
DOI https://dx.doi.org/10.2174/156802612799436678 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration
Current Medicinal Chemistry Antiviral Immunotherapy for Mosquito-Borne Flaviviruses: A Review of Current Status
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) HIV-1, Methamphetamine and Astrocyte Glutamate Regulation: Combined Excitotoxic Implications for Neuro-AIDS
Current HIV Research Readjusting the Glucocorticoid Balance: An Opportunity for Modulators of 11β -Hydroxysteroid Dehydrogenase Type 1 Activity?
Endocrine, Metabolic & Immune Disorders - Drug Targets Resistance to Apoptosis: Mechanism for the Development of HIV Reservoirs
Current HIV Research Substance Abuse, HIV-1 and Hepatitis
Current HIV Research Epigenetic Control of MicroRNA Expression and Aging
Current Genomics Allosteric Inhibitors of SHP2: An Updated Patent Review (2015-2020)
Current Medicinal Chemistry Reproductive Effects of Low-to-Moderate Medical Radiation Exposure
Current Medicinal Chemistry Bile Acids and Derivatives, Their Nuclear Receptors FXR, PXR and Ligands: Role in Health and Disease and Their Therapeutic Potential
Anti-Cancer Agents in Medicinal Chemistry Cancer Chemoprevention by Targeting the Epigenome
Current Drug Targets Rational Targeting of Peroxisome Proliferating Activated Receptor Subtypes
Current Medicinal Chemistry Biomarkers in Post-stroke Depression
Current Neurovascular Research Role of Tyrosine Phosphatase Inhibitors in Cancer Treatment with Emphasis on SH2 Domain-Containing Tyrosine Phosphatases (SHPs)
Anti-Cancer Agents in Medicinal Chemistry The Secreted Aspartic Proteinases as a New Target in the Therapy of Candidiasis
Current Drug Targets Angiogenesis as Risk Factor for Plaque Vulnerability
Current Pharmaceutical Design Discoveries of Tat-TAR Interaction Inhibitors for HIV-1
Current Drug Targets - Infectious Disorders HIV-1 TAT and IMMUNE DYSREGULATION in AIDS PATHOGENESIS: a THERAPEUTIC TARGET
Current Drug Targets Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers
Current Topics in Medicinal Chemistry Are We There Yet? The Clinical Potential of Intranasal Oxytocin in Psychiatry
Current Psychiatry Reviews