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

Scientific reports, 2016-01, Vol.6 (1), p.19008-19008, Article 19008 [Peer Reviewed Journal]

Copyright Nature Publishing Group Jan 2016 ;Copyright © 2016, Macmillan Publishers Limited 2016 Macmillan Publishers Limited ;ISSN: 2045-2322 ;EISSN: 2045-2322 ;DOI: 10.1038/srep19008 ;PMID: 26740187

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Title:
Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists
Author: Sepe, Valentina ; Festa, Carmen ; Renga, Barbara ; Carino, Adriana ; Cipriani, Sabrina ; Finamore, Claudia ; Masullo, Dario ; Del Gaudio, Federica ; Monti, Maria Chiara ; Fiorucci, Stefano ; Zampella, Angela
Subjects: Acids ; Animals ; Bile ; Bile acids ; Cholic Acids - chemical synthesis ; Cholic Acids - pharmacology ; Drug Evaluation, Preclinical ; HEK293 Cells ; Hep G2 Cells ; Humans ; Inhibitory Concentration 50 ; Liver diseases ; Mice, Inbred C57BL ; Receptors, Cytoplasmic and Nuclear - agonists ; Receptors, Cytoplasmic and Nuclear - metabolism ; Receptors, G-Protein-Coupled - agonists ; Side effects ; Transcriptional Activation - drug effects
Is Part Of: Scientific reports, 2016-01, Vol.6 (1), p.19008-19008, Article 19008
Description: Bile acids are the endogenous modulators of the nuclear receptor FXR and the membrane receptor GPBAR1. FXR represents a promising pharmacological target for the treatment of cholestatic liver disorders. Currently available semisynthetic bile acid derivatives cover the same chemical space of bile acids and therefore they are poorly selective toward BA receptors, increasing patient risk for adverse side effects. In this report, we have investigated around the structure of CDCA describing the synthesis and the in vitro and in vivo pharmacological characterization of a novel family of compounds modified on the steroidal tetracyclic core and on the side chain. Pharmacological characterization resulted in the identification of several potent and selective FXR agonists. These novel agents might add utility in the treatment of cholestatic disorders by potentially mitigating side effects linked to unwanted activation of GPBAR1.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 2045-2322
EISSN: 2045-2322
DOI: 10.1038/srep19008
PMID: 26740187
Source: MEDLINE
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Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists

Copyright Nature Publishing Group Jan 2016 ;Copyright © 2016, Macmillan Publishers Limited 2016 Macmillan Publishers Limited ;ISSN: 2045-2322 ;EISSN: 2045-2322 ;DOI: 10.1038/srep19008 ;PMID: 26740187

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