Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

Yuan, Fang; Hegazy, Lamees; Finck, Brian N.; Elgendy, Bahaa

doi:10.1021/acs.jmedchem.1c01017

Cited by 28 publications

(40 citation statements)

References 113 publications

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“…A large number of FXR ligands, especially agonists, have been developed for the intervention of NASH in the past decade. 39 However, the constant challenge associated with dyslipidemia and pruritus still hinders drug development in this area. Recent research demonstrated that intestinal selective FXR antagonism led to beneficial phenotypes such as controlled body weight, remission of insulin resistance, and improved liver morphology.…”

Section: ■ Discussionmentioning

confidence: 99%

Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis

Zhang

Liu

Wang³

et al. 2022

J. Med. Chem.

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Farnesoid X receptor (FXR) has emerged as a promising therapeutic target for nonalcoholic steatohepatitis (NASH) because of its tightly interwoven relationship with bile acid homeostasis, inflammation, fibrosis, and glucose and lipid metabolism. Evidence showed that intestinal FXR antagonism exhibited remarkable metabolic improvements in mice. Herein, we developed a series of betulinic acid derivatives as potent intestinal FXR antagonists, and F6 was identified as the most potent one with an IC50 at 2.1 μM. F6 selectively inhibited intestinal FXR signaling and ameliorated the hepatic steatosis, inflammation, and fibrosis in Gubra-amylin NASH (GAN) and high-fat with methionine and choline deficiency (HFMCD) diet-induced NASH models. The beneficial effects were achieved by direct antagonism of intestinal FXR and feedback activation of hepatic FXR, thereby decreasing ceramides and repressing inflammasome activation in the liver. Collectively, our work substantially supports F6 as a promising drug candidate against NASH and demonstrates that antagonism of intestinal FXR signaling is a practical strategy for treating metabolic diseases.

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Section: ■ Discussionmentioning

confidence: 99%

Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis

Zhang

Liu

Wang³

et al. 2022

J. Med. Chem.

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“…Despite NAFLD being one of the fastest growing diseases, continued research is needed to elucidate the biological mechanisms underlying NAFLD to develop novel therapeutic interventions [24] . Multiple recent reviews have summarized the potential therapeutic and diagnostic value in targeting components of bile acid and sphingolipid metabolism [15,23,72–75] . Therapeutics which target different components of bile acid metabolism can have unanticipated effects on glucose homeostasis or lipid metabolism, but adverse side effects are mostly isolated to gastointestinal dysregulation [76] .…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

“…[24] Multiple recent reviews have summarized the potential therapeutic and diagnostic value in targeting components of bile acid and sphingolipid metabolism. [15,23,[72][73][74][75] Therapeutics which target different components of bile acid metabolism can have unanticipated effects on glucose homeostasis or lipid metabolism, but adverse side effects are mostly isolated to gastointestinal dysregulation. [76] However, bile acid pathways appear to be a sensible pharmacologic target.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Bile acids and sphingolipids in non-alcoholic fatty liver disease

Jackson

Way

Zhou

2022

Chinese Medical Journal

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Non-alcoholic fatty liver disease (NAFLD) is one of the fastest-growing diseases, and its global prevalence is estimated to increase >50% by 2030. NAFLD is comorbid with metabolic syndrome, obesity, type 2 diabetes, and insulin resistance. Despite extensive research efforts, there are no pharmacologic or biological therapeutics for the treatment of NAFLD. Bile acids and sphingolipids are well-characterized signaling molecules. Over the last few decades, researchers have uncovered potential mechanisms by which bile acids and sphingolipids regulate hepatic lipid metabolism. Dysregulation of bile acid and sphingolipid metabolism has been linked to steatosis, inflammation, and fibrosis in patients with NAFLD. This clinical observation has been recapitulated in animal models, which are well-accepted by experts in the hepatology field. Recent transcriptomic and lipidomic studies also show that sphingolipids are important players in the pathogenesis of NAFLD. Moreover, the identification of bile acids as activators of sphingolipid-mediated signaling pathways established a novel theory for bile acid and sphingolipid biology. In this review, we summarize the recent advances in the understanding of bile acid and sphingolipid-mediated signaling pathways as potential contributors to NAFLD. A better understanding of the pathologic effects mediated by bile acids and sphingolipids will facilitate the development of new diagnostic and therapeutic strategies for NAFLD.

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“…Therefore, FXR agonist has great therapeutic potential on many indications, and several agonists have been reached in clinical tests, such as Obeticholic acid and Cilofexor (Figure 1). [5] However, the structure types of existing agonists are relatively simple, which is often derived from cholic acid and isoxazole series [5c] . Thus, the new FXR agonists with different structure types needed to be explored.…”

Section: Introductionmentioning

confidence: 99%

Structure‐Based Optimization of Novel Farnesoid X Receptor Agonist for the Treatment of Acetaminophen‐Induced Liver Injury

et al. 2022

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Farnesoid X receptor (FXR) plays an important role in regulating glucolipid metabolism, detoxification, and inflammation in liver. Thus, FXR has huge potential on several liver diseases, including drug‐induced liver injury, fibrosis, and fatty liver. In this study, we performed a structure‐based drug design strategy to optimize the previous reported FXR agonist N‐(2‐methoxy‐4‐nitrophenyl)‐2‐((2‐(2‐oxopyrrolidin‐1‐yl)phenyl)amino)acetamide (1). After structure‐based drug design, the optimal compound, 3‐(2‐((2‐(2‐oxopyrrolidin‐1‐yl)phenyl)amino)acetamido)benzoic acid (2, EC50=2.43 μM), was identified by displacing the potentially toxic nitro group of compound 1 with carboxylic acid to obtain new ionic bond with His294. Compound 2 revealed considerable activity on FXR, and exerts best therapeutic effects on alleviating acetaminophen‐induced liver damages in this series by up‐regulation of FXR‐related gene expression in vivo. In summary, these results suggest that compound 2 is a promising FXR agonist suitable for further evaluation.

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Recent Advances in the Medicinal Chemistry of Farnesoid X Receptor

Cited by 28 publications

References 113 publications

Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis

Discovery of Betulinic Acid Derivatives as Potent Intestinal Farnesoid X Receptor Antagonists to Ameliorate Nonalcoholic Steatohepatitis

Bile acids and sphingolipids in non-alcoholic fatty liver disease

Structure‐Based Optimization of Novel Farnesoid X Receptor Agonist for the Treatment of Acetaminophen‐Induced Liver Injury

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