Farnesoid X receptor modulators: a patent review

Abstract

Importance of the field: The farnesoid X receptor (FXR) is a key regulator of cholesterol homeostasis, triglyceride synthesis and lipogenesis. Given some patients' inability to tolerate existing medications, such as the statins, for cholesterol reduction, there is a pressing need for additional medicines to treat dyslipidemia. FXR agonists have emerged in discovery and preclinical efforts to show great potential for the treatment of these and other life-impairing and life-threatening conditions.

Areas covered in this review: Recent advances in the search for novel FXR modulators are reviewed, with a particular focus on patent applications and peer-reviewed publications disclosed in the past 5 years.

What the reader will gain: A total of 72 patent applications and peer-reviewed articles, containing 16 generic structure classes with nearly 5000 novel synthesized structures are reviewed. Where possible, the structure–activity relationship of these structure classes is surveyed, new insights into in vitro and in vivo efficacy of FXR agonists are disclosed, and potential new and promising therapeutic applications are revealed.

Take home message: FXR agonists have proven their efficacy and safety in primates and have significant potential as therapeutic agents for the treatment of dyslipidemia and potentially an array of other disease areas.

Keywords::

• bile acid
• dyslipidemia
• farnesoid X receptor
• liver disease
• metabolic disease
• nuclear hormone receptor

Acknowledgements

The advice and mentorship of my former biology colleagues at Wyeth, DC Harnish and MJ Evans, was critical in allowing me to work effectively as a chemistry team leader in the FXR modulator area and develop a strong understanding of its intricacies. The support and understanding of my significant other and children for me to continue to pursue expertise and experience in this area despite the withdrawal of my former employer and other pharmaceutical companies from this area has been invaluable and is deeply appreciated.

Notes

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