Literature DB >> 35217809

FXR: structures, biology, and drug development for NASH and fibrosis diseases.

Si-Yu Tian1, Shu-Ming Chen1, Cheng-Xi Pan1, Yong Li2.   

Abstract

The nuclear receptor farnesoid-X-receptor (FXR) plays an essential role in bile acid, glucose, and lipid homeostasis. In the last two decades, several diseases, such as obesity, type 2 diabetes, nonalcoholic fatty liver disease, cholestasis, and chronic inflammatory diseases of the liver and intestine, have been revealed to be associated with alterations in FXR functions. FXR has become a promising therapeutic drug target, particularly for enterohepatic diseases. Despite the large number of FXR modulators reported, only obeticholic acid (OCA) has been approved for primary biliary cholangitis (PBC) therapy as FXR modulator. In this review, we summarize the structure and function of FXR, the development of FXR modulators, and the structure-activity relationships of FXR modulators. Based on the structural analysis, we discuss potential strategies for developing future therapeutic FXR modulators to overcome current limitations, providing new perspectives for enterohepatic and metabolic diseases treatment.
© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Entities:  

Keywords:  FXR modulators; farnesoid X receptor; liver fibrosis diseases; nuclear receptor; rational drug design; structure–activity relationships

Mesh：

Year:  2022        PMID： 35217809      PMCID： PMC9061771          DOI： 10.1038/s41401-021-00849-4

Source DB:  PubMed          Journal:  Acta Pharmacol Sin        ISSN： 1671-4083            Impact factor:   7.169


  91 in total

Review 1.  How many drug targets are there?

Authors:  John P Overington; Bissan Al-Lazikani; Andrew L Hopkins
Journal:  Nat Rev Drug Discov       Date:  2006-12       Impact factor: 84.694

2.  Bile acids: natural ligands for an orphan nuclear receptor.

Authors:  D J Parks; S G Blanchard; R K Bledsoe; G Chandra; T G Consler; S A Kliewer; J B Stimmel; T M Willson; A M Zavacki; D D Moore; J M Lehmann
Journal:  Science       Date:  1999-05-21       Impact factor: 47.728

Review 3.  Future trends in the treatment of non-alcoholic steatohepatitis.

Authors:  Stefano Fiorucci; Michele Biagioli; Eleonora Distrutti
Journal:  Pharmacol Res       Date:  2018-07-17       Impact factor: 7.658

4.  Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates.

Authors:  Joseph T Lundquist; Douglas C Harnish; Callain Y Kim; John F Mehlmann; Rayomand J Unwalla; Kristin M Phipps; Matthew L Crawley; Thomas Commons; Daniel M Green; Weixin Xu; Wah-Tung Hum; Julius E Eta; Irene Feingold; Vikram Patel; Mark J Evans; Kehdih Lai; Lisa Borges-Marcucci; Paige E Mahaney; Jay E Wrobel
Journal:  J Med Chem       Date:  2010-02-25       Impact factor: 7.446

5.  Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

Authors:  Sama I Sayin; Annika Wahlström; Jenny Felin; Sirkku Jäntti; Hanns-Ulrich Marschall; Krister Bamberg; Bo Angelin; Tuulia Hyötyläinen; Matej Orešič; Fredrik Bäckhed
Journal:  Cell Metab       Date:  2013-02-05       Impact factor: 27.287

Review 6.  Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease.

Authors:  Emina Halilbasic; Claudia Fuchs; Stefan Traussnigg; Michael Trauner
Journal:  Dig Dis       Date:  2016-06-22       Impact factor: 2.404

7.  Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis.

Authors:  Songwen Zhang; Juan Wang; Qiangyuan Liu; Douglas C Harnish
Journal:  J Hepatol       Date:  2009-05-18       Impact factor: 25.083

8.  Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia.

Authors:  Michael J Genin; Ana B Bueno; Javier Agejas Francisco; Peter R Manninen; Wayne P Bocchinfuso; Chahrzad Montrose-Rafizadeh; Ellen A Cannady; Timothy M Jones; John R Stille; Eyas Raddad; Charles Reidy; Amy Cox; M Dodson Michael; Laura F Michael
Journal:  J Med Chem       Date:  2015-12-02       Impact factor: 7.446

9.  A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.

Authors:  Michael Downes; Mark A Verdecia; A J Roecker; Robert Hughes; John B Hogenesch; Heidi R Kast-Woelbern; Marianne E Bowman; Jean-Luc Ferrer; Andrew M Anisfeld; Peter A Edwards; John M Rosenfeld; Jacqueline G A Alvarez; Joseph P Noel; K C Nicolaou; Ronald M Evans
Journal:  Mol Cell       Date:  2003-04       Impact factor: 17.970

Review 10.  Bile Acid Nuclear Receptor Farnesoid X Receptor: Therapeutic Target for Nonalcoholic Fatty Liver Disease.

Authors:  Sun Gi Kim; Byung Kwon Kim; Kyumin Kim; Sungsoon Fang
Journal:  Endocrinol Metab (Seoul)       Date:  2016-12
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  2 in total

Review 1.  Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota.

Authors:  Hideki Mori; Gianluca Svegliati Baroni; Marco Marzioni; Francesca Di Nicola; Pierangelo Santori; Luca Maroni; Ludovico Abenavoli; Emidio Scarpellini
Journal:  Metabolites       Date:  2022-07-14

Review 2.  Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease.

Authors:  Liangliang Zhou; Haiyuan Shen; Xiaofeng Li; Hua Wang
Journal:  Front Immunol       Date:  2022-07-22       Impact factor: 8.786
  2 in total

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