Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists

Scientific Reports

Volumn 6, Issue , 2016, Pages

  Sepe, Valentina ^a   Festa, Carmen ^a   Renga, Barbara ^b   Carino, Adriana ^b   Cipriani, Sabrina ^b   Finamore, Claudia ^a   Masullo, Dario ^a   Del Gaudio, Federica ^c   Monti, Maria Chiara ^c   Fiorucci, Stefano ^b   Zampella, Angela ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b Nuova Facoltà di Medicina   (Italy)

^c UNIVERSITY OF SALERNO   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CELL RECEPTOR; CHOLIC ACID DERIVATIVE; FARNESOID X-ACTIVATED RECEPTOR; G PROTEIN COUPLED RECEPTOR; GPBAR1 PROTEIN, HUMAN;

AGONISTS; ANIMAL; C57BL MOUSE; DRUG EFFECTS; HEK293 CELL LINE; HEP-G2 CELL LINE; HUMAN; IC50; METABOLISM; PRECLINICAL STUDY; SYNTHESIS; TRANSCRIPTION INITIATION;

ANIMALS; CHOLIC ACIDS; DRUG EVALUATION, PRECLINICAL; HEK293 CELLS; HEP G2 CELLS; HUMANS; INHIBITORY CONCENTRATION 50; MICE, INBRED C57BL; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, G-PROTEIN-COUPLED; TRANSCRIPTIONAL ACTIVATION;

EID: 84954162202     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep19008     Document Type: Article

References (25)

1. Makishima M., et al. Identification of a nuclear receptor for bile acids. Science. 284, 1362-1365 (1999
2. Parks D. J., et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 284, 1365-1368 (1999
3. Goodwin B., et al A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6. 517-526 (2000
4. Fiorucci S., & Baldelli F. Farnesoid X receptor agonists in biliary tract disease. Curr. Opin. Gastroenterol. 25, 252-259 (2009
5. Fiorucci S., et al. Targeting FXR in cholestasis: hype or hope. Expert Opin. Ther. Targets. 12, 1449-1459 (2014
6. Fiorucci S., Mencarelli A., Distrutti E., & Zampella A. Farnesoid X receptor: from medicinal chemistry to clinical applications. Future Med. Chem. 4, 877-891 (2012
7. Cipriani S., Mencarelli A., Palladino G., & Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid Res. 51, 771-784 (2010
8. Rizzo G., et al. The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo. Mol. Pharmacol. 70, 1164-1173 (2006
9. Fiorucci S., Rizzo G., Donini A., Distrutti E., & Santucci L. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol. Med. 13, 298-309 (2007
10. Mencarelli A., et al. Dissociation of intestinal and hepatic activities of FXR and LXRa supports metabolic effects of terminal ileum interposition in rodents. Diabetes. 62, 3384-3393 (2013
11. Wang H., Chen J., Hollister K., Sowers L. C., & Forman B. M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3. 543-553 (1999
12. Maruyama T., et al. Identification of membrane type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714-719 (2002
13. Fiorucci S., Mencarelli A., Palladino G., & Cipriani S. Bile-Acid activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol. Sci. 30, 570-580 (2009
14. Fiorucci S., Cipriani S., Baldelli F., & Mencarelli A. Bile acid activated receptors in the treatment of dyslipidemia and related disorders. Prog. Lipid Res. 49, 171-185 (2010
15. Tiwari A., & Maiti P. TGR5: an emerging bile acid G-protein coupled receptor target for the potential treatment of metabolic disorders. Drug Discovery Today. 14, 523-530 (2009
16. Alemi F., et al. The TGR5 receptor mediates bile acid-induced itch and analgesia. J. Clin. Invest. 123, 1513-1530 (2013
17. Festa C., et al. Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands. J. Med. Chem. 57, 8477-8495 (2014
18. Sepe V., Distrutti E., Limongelli V., Fiorucci S., & Zampella A. Steroidal scaffolds as FXR and GPBAR1 ligands: from chemistry to therapeutical application. Future Med. Chem. 7, 1109-1135 (2015
19. Sato H., et al. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-Activity relationships, and molecular modeling studies. J. Med. Chem. 51, 1831-1841 (2008
20. Rizzo G., et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol. Pharmacol. 78, 617-630 (2010
21. Pellicciari R., et al. Nongenomic actions of bile acids. Synthesis and preliminary characterization of 23- And 6,23-Alkyl-substituted bile acid derivatives as selective modulators for the G-protein coupled receptor TGR5. J. Med. Chem. 50, 4265-4268 (2007
22. Hirschfield G. M., et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 148, 751-761 (2015
23. Neuschwander-Tetri B. A., et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-Alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 385, 956-965 (2015
24. Fiorucci S., et al. Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA. Mini-Rev. Med. Chem. 11, 753-762 (2011
25. Mi L. Z., et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell. 11, 1093-1100 (2003