Farnesoid X receptor modulators 2014-present: a patent review

ABSTRACT

Introduction. The nuclear receptor FXR regulates the expression of genes involved in bile acids, glucose and lipid homeostasis. For its role as guardian of metabolism, FXR has been identified a promising pharmacological target in liver bile acid and lipid accumulation, such as cholestasis and non-alcoholic fatty liver disease (NAFLD). The field of FXR research is extremely competitive with a large number of patents and articles published in the last decades identifying promising hit compounds.

Areas covered. The present review summarizes recent patent activity (2014-to date) filing for synthetic and natural FXR ligands, including bile acid derivatives and non-steroidal compounds, alongside their in vitro and in vivo efficacy as well as their therapeutic applications.

Expert opinion. While the first FXR agonist, obeticholic acid, has gained approval, significant safety issues have been emerged. Today is unclear whether these safety issues are class related or restricted to the bile acid scaffold of this agent. Despite the significant number of patent applications claiming steroidal and non-steroidal FXR agonists, several questions on their therapeutic potential in cholestasis and NASH remain open leaving a space for the development of novel compounds.

KEYWORDS:

• FXR
• steroidal agonists
• non-steroidal agonists
• primary biliary cirrhosis (PBC)
• non-alcoholic steatohepatitis (NASH)

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• FXR is a promising target in liver bile acid and lipid accumulation, such as cholestasis and non-alcoholic steatohepatitis (NASH).

• The review covers the recent progress (2014-to date) in the identification of FXR ligands alongside theirtherapeutic applications.

• Several pharmaceutical companies were actively engaged in 2014-to date in the discovery of new drugs to treat NASH through FXR modulation.

• Two research directives have been pursued in identifying FXR ligands, mainly focused on bile-acid like and aromatic scaffolds.

• FXR agonists based on a bile acid structure have gain approval, but are hampered by the appearance of severe side effects.

Results from clinical studies are needed to clarify whether nonsteroidal-FXR ligands are useful in the pharmacological treatment of NASH

Additional information

Funding

This paper has not been funded.