Patented Farnesoid X receptor modulators: a review (2019 – present)

ABSTRACT

Introduction

The Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer.

Areas covered

Recent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past 5 years related to both the discovery and development of FXR targeting drugs.

Expert Opinion

FXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators.

KEYWORDS:

• Bile acids
• cancer
• Farnesoid X receptor
• nonalcoholic fatty liver diseases
• steatohepatitis
• primary biliary cirrhosis
• process chemistry
• structure–activity relationships

Article highlights

• FXR has become a promising therapeutic target for the treatment of several diseases, such as nonalcoholic fatty liver disease, cholestasis, obesity, type 2 diabetes, and chronic inflammatory diseases of the liver and intestine.

• Despite the large number of FXR modulators disclosed, only obeticholic acid (OCA, Ocaliva) has been approved for primary biliary cholangitis therapy as FXR agonist.

• This review covers recent advances in the field of FXR modulators with a focus on patents filed in the past five years (2019-to date) concerning the discovery and development of FXR targeting drugs.

• The search for novel FXR modulators has been mainly directed towards the exploration of the bile acid scaffold, terpenoids and isoxazoles derivatives.

• Future directions include combination strategies (e.g., FXR/PPARs), tissue-specific and gene-selective FXR modulators.

Declaration of interests

A Gioiello is a cofounder of Tes Pharma. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.