The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease.

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Fiorucci S, Biagioli M, Baldoni M, Ricci P, Sepe V, Zampella A, Distrutti E

The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease.

Expert Opin Drug Discov. 2021 Oct;16(10):1193-1208. doi: 10.1080/17460441.2021.1916465. Epub 2021 May 5.

PubMed ID

33849361 [ View in PubMed

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Abstract

INTRODUCTION: The farnesoid-x-receptor (FXR) is a ubiquitously expressed nuclear receptor selectively activated by primary bile acids. AREA COVERED: FXR is a validated pharmacological target. Herein, the authors review preclinical and clinical data supporting the development of FXR agonists in the treatment of nonalcoholic fatty liver disease. EXPERT OPINION: Development of systemic FXR agonists to treat the metabolic liver disease has been proven challenging because the side effects associated with these agents including increased levels of cholesterol and LDL-c and reduced HDL-c raising concerns over their long-term cardiovascular safety. Additionally, pruritus has emerged as a common, although poorly explained, dose-related side effect with all FXR ligands, but is especially common with OCA. FXR agonists that are currently undergoing phase 2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently being developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cenicriviroc	C-C chemokine receptor type 2	Protein	Humans	Unknown	Inhibitor	Details
Nidufexor	Bile acid receptor	Protein	Humans	Yes	Agonist	Details
Tropifexor	Bile acid receptor	Protein	Humans	Unknown	Agonist Binder	Details