Potent Farnesoid X Receptor Agonist Research Articles

A Short Review on Obeticholic Acid: An Effective Modulator of Farnesoid X Receptor.

Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.

Enteral Agonism of the Farnesoid X Receptor-Fibroblast Growth Factor 19 Axis Prevents Cholestasis in TPN-Fed Piglets

Total parenteral nutrition (TPN) administration provides necessary nutrients to infants who cannot tolerate enteral feedings. However, the use of TPN can result in cholestasis which can cause parenteral nutrition-associated liver diseases. Previous mitigation strategies for cholestasis have included administering bile acids enterally to encourage normal bile acid metabolism. The objective of this study was to determine if treatment of either ursodeoxycholic acid (UDCA), Tropifexor (TPX), or fibroblast growth factor 19 (FGF19) will prevent cholestasis in a piglet TPN model through the activation of the farnesoid X receptor (FXR)-FGF19 axis. We hypothesize that UDCA will have minimum effects on FXR while TPX, a potent FXR agonist, will significantly affect the FXR pathway, and FGF19 will reduce bile acid synthesis to alleviate cholestasis. Piglets received TPN for 3 weeks and were treated enterally with either UDCA (25 mg/kg*day) or TPX (7.5 μg/kg*day) with minimal milk-based formula (12 mL/kg*day), or daily intravenous FGF19 (0.25 mg/d) injection. Body weight gain was not different after 3 weeks. Plasma markers of cholestasis such as of total bile acids, bilirubin, and gamma-glutamyl transferase were lower in pigs that received TPX compared to the control treatment at the end of the study. Circulating levels of FGF19 and tissue concentrations of total bile acids were not different across treatments. In the ileum, TPX increased mRNA expression of FGF19, ileal lipid binding protein, and organic solute transporter α compared to the control pigs. All treatments reduced the mRNA expression of apical sodium-dependent bile acid transporter compared to the control treatment. TPX also increased mRNA expression of small heterodimer protein and bile salt export pump in the liver. Overall, we conclude that UDCA and FGF19 had minimal effects on cholestasis, whereas TPX prevented cholestasis in part via activation of the FXR-FGF19 axis in TPN fed piglets. NIDDK R01-DK094616 K01 DK129408 T32 NIH grant DK07664. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Discovery of HPG1860, a Structurally Novel Nonbile Acid FXR Agonist Currently in Clinical Development for the Treatment of Nonalcoholic Steatohepatitis.

The farnesoid X receptor (FXR) is a ligand-activated nuclear receptor. Activation of FXR significantly impacts the expressions of the pivotal genes involved in bile acid metabolism, inflammation, fibrosis, and homeostasis of lipid and glucose, leading to considerable interests in developing FXR agonists for the treatment of nonalcoholic steatohepatitis (NASH) or other FXR-relevant diseases. Herein, we describe the design, optimization, and characterization of a series of N-methylene-piperazinyl derivatives as the nonbile acid FXR agonists. Particularly, compound 23 (HPG1860), a potent full FXR agonist, shows high selectivity, favorable ADME and pharmacokinetics profile, along with favorable in vivo activities demonstrated in both rodent PD model and HFD-CCl4 model and is currently in clinical development in patients with NASH in phase II.

Role of Fasting Mimicking Diet in Farnesoid x Receptor for Suppressing Epithelial-to-Mesenchymal Transition, Cell Cycle Progression, and Viability of Prostate Cancer Cells

The systemic and resistant nature of metastatic castration-resistant prostate cancers (mCRPC) renders it largely incurable even after intensive multimodal therapy. Proliferation, survival, and epithelial-mesenchymal transition (EMT) are three fundamental events that are deeply linked to carcinogenesis. Hence, it is necessary to find a new combination of several therapies, targeting those vital mechanisms without causing side effects. Significant research works have shown differential low expression of the metabolic Farnesoid X receptor (FXR) in primary and metastatic prostate cancer suggesting their importance in prostate pathogenesis. Obticholic acid (INT 747), a potent FXR agonist is widely used in primary biliary cholangitis, and Fasting mimicking Diet (FMD) both were drastically showed effects on different cancer progression. We hypothesized that FXR and FMD may inhibit proliferation and the metastatic phenotype in PC-3 prostate cancer cells. Analyses of the cell viability, cell cycle, migration, and matrigel invasion assays were performed to elucidate how INT 747 and /or FMD functions in prostate cancer. In this study, INT 747 treatment caused apoptotic morphological changes and significantly reduced the survival of PC-3 cells incubated in normal mediums. Furthermore, we showed that the combination of the INT 747 and FMD was much more harmful to cancer cells than the treatment with INT 747 or FMD alone. Moreover, our study showed that INT 747 either alone or combined with FMD robustly induced cell cycle arrest at the S phase. Interestingly, the combination treatment on PC-3 cells not only showed several lines of evidence of apoptotic cells death but also inhibited carcinogenic potential as evaluated by impairment of spheroid formation capacity and delayed wound healing and matrigel invasion. At the cellular level, FXR activation resulted in down-regulation of procaspase -3, vimentin, and MMP9, which triggers apoptotic cell death, cell cycle arrest, and switch from mesenchymal to an epithelial phenotype. Collectively, FXR activation alone markedly decreases, and when combined with FMD abrogates the survival and carcinogenic potential of metastatic prostate cancer cells.

Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies.

Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment.

Machine learning- and structure-based discovery of a novel chemotype as FXR agonists for potential treatment of nonalcoholic fatty liver disease

Farnesoid X receptor (FXR) is a promising target for drug discovery against nonalcoholic fatty liver disease (NAFLD). However, no FXR agonist has been approved for NAFLD so far. The R & D of FXR agonists are somewhat hindered by the lack of effective and safe chemotypes. To this end, we developed a multi-stage computational workflow to screen the Specs and ChemDiv chemical library for FXR agonists, which consisted of machine learning (ML)-based classifiers, shape-based and electrostatic-based models, a FRED-based molecular docking protocol, an ADMET prediction protocol and substructure search. As a result, we identified a novel chemotype that has never been reported before, with compound XJ02862 (ChemDiv ID: Y020-6413) as the representative. By designing an asymmetric synthesis strategy, we were able to prepare four isomers of compound XJ02862. Interestingly, one of the isomers, 2-((S)-1-((2S,4R)-2-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)-1-oxopropan-2-yl)hexahydro-1H-isoindole-1,3(2H)-dione (XJ02862-S2), showed potent FXR agonistic activity in HEK293T cells. The molecular docking, molecular dynamics simulations and site-directed mutagenesis suggested the hydrogen bond between compound XJ02862-S2 and HIS294 of FXR is essential for ligand binding. We further demonstrated that compound XJ02862-S2 had no agonistic effect on TGR5. Further biological experiments have shown that compound XJ02862-S2 could ameliorate hypercholesterolemia, hepatic steatosis, hyperglycemia, insulin resistance (IR) in high-fat-diet induced obese (DIO) mice. In term of molecular mechanism, compound XJ02862-S2 regulates the expression of FXR downstream genes involved in lipogenesis, cholesterol transport and bile acid biosynthesis and transport. Taken together, we have discovered a novel chemotype as potent FXR agonists for NAFLD by computational modeling, chemical synthesis and biological evaluation.

Myclobutanil-mediated alteration of liver-gut FXR signaling in mice.

The effects of exposure to Myclobutanil, a triazole fungicide, on the development and progression of nonalcoholic fatty liver disease (NAFLD) are unclear, but activation of nuclear receptors (NRs) is a known mechanism of azole-induced liver toxicity. Farnesoid X receptor (FXR) is a NR and is highly expressed in the liver and intestine. Activation of FXR tightly regulates bile acid (BA), lipid and glucose homeostasis, and inflammation partly through the induction of fibroblast growth factor 15 (FGF15; human ortholog FGF19). FXR activation is downregulated during NAFLD and agonists are currently being explored as potential therapeutic strategy. In this study, we aimed to clarify the effects of Myclobutanil exposure on FXR activation and NAFLD development. Reporter assay showed Myclobutanil treatment, following FXR activation with potent FXR agonist (GW4064), resulted in a dose-dependent decrease of FXR activity. Furthermore, a 10-day study in male mice demonstrated that cotreatment with Myclobutanil led to an 80% reduction of GW4064-induced ileal expression of Fgf15. In a diet-induced NAFLD study, low-fat diet (LFD) fed mice administered myclobutanil displayed decreased FXR activity in the liver and ileum, while high-fat-high-sugar-diet (HFHSD) fed mice showed an increase in hepatic FXR activity and an induction of target genes regulated by constitutive androstane receptor and/or pregnane X receptor. Our work demonstrates Myclobutanil inhibits FXR activity and modulates FXR activity differentially in mice fed LFD or HFHSD. Our studies suggest the importance of understanding how Myclobutanil could contribute to BA dysregulation in disease states such as NAFLD.

Biomimetic Total Synthesis and the Biological Evaluation of Natural Product (-)-Fargesone A as a Novel FXR Agonist.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays an important role in maintaining or reversing metabolic homeostasis during the development of liver diseases. However, developing FXR modulators to intervene in FXR-related diseases is still an unmet clinical need. Therefore, it is significant to develop novel small-molecule agonists for drug discovery targeting FXR. Through a high-throughput chemical screen and follow-up biological validations, we first identified the natural product Fargesone A (FA) as a potent and selective FXR agonist. The limited, variable supply of FA from natural product isolation, however, has impeded its biological exploration and potential drug development. Accordingly, we have developed a biomimetic and scalable total synthesis of FA in nine steps that provides a solution to the supply of FA. Enabled by chemical synthesis, the in vivo efficacy of FA has been further investigated. The results showed that FA alleviates hepatocyte lipid accumulation and cell death in an FXR-dependent manner. Moreover, treatment of bile duct ligation (BDL)-induced liver disorder with FA ameliorates pathological features in mice. Therefore, our work lays the foundation to develop new small-molecule FXR agonists as a potential therapy for liver diseases.

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells.

Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15 μM/EC50 = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.

Design, synthesis, and biological evaluation of novel FXR agonists based on auraptene

Farnesoid X receptor (FXR) has been considered as an attractive target for metabolic disorder and liver injury, while many current FXR agonists suffer from undesirable side effects, such as pruritus. Therefore, it is urgent to develop new structure types different from current FXR agonists. In this study, a series of structural optimizations were introduced to displace the unstable coumarin and geraniol scaffolds of auraptene (AUR), a novel and safe FXR agonist. All of these efforts led to the identification of compound 14, a potent FXR agonist with nearly fourfold higher activity than AUR. Molecular modeling study suggested that compound 14 fitted well with binding pocket, and formed the key ionic bond with His291 and Arg328. In acetaminophen-induced acute liver injury model, compound 14 exerts better therapeutic effect than that of AUR, which highlighting its pharmacological potential in the treatment of drug-induced liver injury.

Structural basis of tropifexor as a potent and selective agonist of farnesoid X receptor

Farnesoid X receptor (FXR) is considered as a potential target for the treatment of several liver disorders such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Tropifexor is a highly potent and non-steroidal FXR agonist that has progressed into phase II clinical trials in patients with PBC. The clinical trials demonstrate that tropifexor improved serum markers of patients with liver diseases and lower side effect such as pruritus that might be implicated with TGR5 activation. However, the molecular mechanism of the potency and selectivity of tropifexor remains unclear. In this study, the binding affinity of FXR and tropifexor is measured by isothermal titration calorimetry (ITC) assays. The crystal structure of the FXR/tropifexor complex is determined at 2.7 Å resolution to explain the molecular mechanism of tropifexor bound to FXR-LBD. Structural comparison with other FXR/agonists structures reveals the conformational change in the FXR/tropifexor structure. Moreover the structural superposition of TGR5/tropifexor indicates that the steric hindrance between tropifexor and TGR5 might be a possible explanation for the impotency arises of tropifexor to TGR5. Overall, our analyses might provide an insight into the molecular mechanism of tropifexor binding to FXR-LBD and account for the high selectivity of tropifexor for FXR versus TGR5.

Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator

Farnesoid X receptor (FXR) agonists are emerging as potential therapeutics for the treatment of various metabolic diseases, as they display multiple effects on bile acid, lipid, and glucose homeostasis. Although the steroidal obeticholic acid, a full FXR agonist, was recently approved, several side effects probably due to insufficient pharmacological selectivity impede its further clinical application. Activating FXR in a partial manner is therefore crucial in the development of novel FXR modulators. Our efforts focusing on isoxazole-type FXR agonists, common nonsteroidal agonists for FXR, led to the discovery a series of novel FXR agonists bearing aryl urea moieties through structural simplification of LJN452 (phase 2). Encouragingly, compound 11k was discovered as a potent FXR agonist which exhibited similar FXR agonism potency but lower maximum efficacy compared to full agonists GW4064 and LJN452 in cell-based FXR transactivation assay. Extensive invitro evaluation further confirmed partial efficacy of 11k in cellular FXR-dependent gene modulation, and revealed its lipid-reducing activity. More importantly, orally administration of 11k in mice exhibited desirable pharmacokinetic characters resulting in promising invivo FXR agonistic activity.

Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis.

Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, and metabolism of lipid and glucose and becomes a promising therapeutic target for nonalcoholic steatohepatitis (NASH) or other FXR-dependent diseases. The phase III trial results of obeticholic acid demonstrate that the FXR agonists emerge as a promising intervention in patients with NASH and fibrosis, but this bile acid-derived FXR agonist brings severe pruritus and an elevated risk of cardiovascular disease for patients. Herein, we reported our efforts in the discovery of a series of non-bile acid FXR agonists, and 36 compounds were designed and synthesized based on the structure-based drug design and structural optimization strategies. Particularly, compound 42 is a highly potent and selective FXR agonist, along with good pharmacokinetic profiles, high liver distribution, and preferable in vivo efficacy, indicating that it is a potential candidate for the treatment of NASH or other FXR-dependent diseases.

Pyridoxal isonicotinoyl hydrazone inhibition of FXR is involved in the pathogenesis of isoniazid-induced liver injury

Isoniazid (INH)-induced liver injury may be associated with inhibition of the liver farnesoid X receptor (FXR). However, the relationship between FXR and INH-induced liver injury remained unclear. The present study was performed to clarify the role of inhibition of FXR in the pathogenesis of INH-induced liver injury and to further identify potential inhibitors of FXR from INH and its metabolites. HepaRG cells were treated with INH (10 mM) plus mixed bile acids (BA) and rats were treated with INH (60–600 mg/kg p.o.) or INH plus obeticholic acid (OCA, 10 mg/kg), a potent FXR agonist, for seven days. INH can cause BA-dependent toxicity and apoptosis with elevated intracellular bile acids in vitro; indeed, in these studies, liver bile acids and mRNA levels for Cyp7a1, an FXR target gene were increased, while mRNA levels for FXR and Shp were significantly decreased, and these changes could be prevented by co-treatment with the FXR agonist OCA. In silico molecular docking studies showed that INH, acetyl isoniazid, isonicotinic acid and PIH may be potential FXR inhibitors, and a TR-FRET FXR-coactivator assay confirmed that PIH is a strong antagonist of FXR (IC50 = 52 nM). To further determine if PIH also inhibits FXR activity in vivo, rats were treated with PIH directly (5 mg/kg). Liver total bile acids were significantly increased while FXR expression was not changed, but Shp mRNA levels were significantly decreased and Cyp7a1 mRNA was significantly increased, consistent with PIH acting as an FXR antagonist. In summary, PIH inhibition of liver FXR function leading to bile acid accumulation in hepatocytes may be an early pathogenesis event in INH-induced liver injury.

Promotion of lipogenesis by PPARγ-activated FXR expression in adipocytes

Farnesoid X receptor (FXR), a bile acid receptor, is known to be involved in the promotion of adipogenesis. However, the regulation mechanism of FXR-promoted adipogenesis remains unclear. In this study, we investigated the regulation mechanism of FXR-mediated activation of adipogenesis in murine adipocyte 3T3-L1 cells. Chenodeoxycholic acid (CDCA), a potent FXR agonist, enhanced the accumulation of intracellular triglycerides and the expression of the adipogenic and lipogenic genes, while guggulsterone, an FXR antagonist, suppressed CDCA-activated adipogenesis. Moreover, troglitazone, a peroxisome proliferator-activated receptor (PPAR) γ agonist, elevated the expression of the FXR gene during adipogenesis, similar to that of the PPARγ gene. Chromatin immunoprecipitation assay demonstrated that PPARγ bound to the PPAR-responsive element of the FXR gene in a PPARγ agonist-dependent manner. Furthermore, FXR activation induced the expression of the stearoyl-CoA desaturase (SCD) gene in adipocytes. The FXR-response element (FXRE) was found in the SCD gene promoter, and FXR bound to the FXRE of the SCD gene promoter, and its binding efficiency was enhanced by CDCA in adipocytes. These results indicate that FXR assisted lipogenesis through the enhanced expression of SCD in a PPARγ-dependent manner in adipocytes, making this study the first to identify the role of FXR in the promotion of lipogenesis by PPARγ activation.

Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism

Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1–14) and four known analogues (15–18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1–70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC50 = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology.

Obeticholic acid in primary biliary cholangitis: where we stand.

This review will summarize the use of obeticholic acid (OCA) in treatment of primary biliary cholangitis (PBC). It seeks to discuss the mechanism of action, evidence for use, appropriate clinical use, and common adverse effects of OCA. PBC is a chronic, progressive cholestatic liver disease that is a chronic progressive that may lead to end-stage liver disease and need for liver transplantation. Ursodeoxycholic acid (UDCA) has been the mainstay of therapy for PBC for decades. Recent research has led to the discovery that bile acids act as hormones and have many effects, one of which is activating the farnesoid X receptor (FXR). Activation of FXR leads to decreased bile acid synthesis, inflammation, and fibrosis of the liver. OCA is a highly potent FXR agonist. Several clinical trials demonstrated that OCA treatment in PBC led to a significant decrease in serum alkaline phosphatase, a marker for long-term survival. The US FDA-approved OCA in 2016, which led to incorporation of OCA into current guidelines as a second-line treatment for PBC. The most clinically relevant adverse effect of OCA is dose-related pruritus. We review the role of OCA and current guidelines in treatment of PBC.

Characterization of EDP-305, a Highly Potent and Selective Farnesoid X Receptor Agonist, for the Treatment of Non-alcoholic Steatohepatitis

Non-alcoholic steatohepatitis (NASH), characterized by hepatocyte injury, inflammation, and fibrosis, is the main cause of chronic liver disease in the Western world. There are currently no approved pharmacological therapies for NASH, underscoring the urgent need for effective treatments. The farnesoid X receptor (FXR) has emerged as an attractive target for the treatment of metabolic and chronic liver diseases. EDP-305 is an FXR agonist currently in phase 2 clinical trials for Primary Biliary Cholangitis (PBC) and NASH. Here, we demonstrate that EDP-305 is a selective and potent FXR agonist that regulates multiple pathways relevant to NASH progression. EDP-305 exhibits anti-fibrotic and anti-inflammatory gene signatures in human macrophage and stellate cell lines, as well as favorable effects on lipid metabolism in hepatocytes, including enhanced low density lipoprotein (LDL)-cholesterol uptake and decreased triglyceride accumulation. The therapeutic potential of EDP-305 was further evaluated in two murine models of NASH: a streptozotocin-high fat diet STAMTM model and a dietary induced NASH (DIN) model driven by high fat, cholesterol, and fructose feeding. In both NASH models, EDP-305 significantly decreased hepatocyte ballooning and lowered the non-alcoholic fatty liver disease (NAFLD) activity score. EDP-305 also significantly attenuated hepatic steatosis and dyslipidemia observed in the DIN mouse model. Conclusion: EDP-305 is a potent FXR agonist with a favorable gene expression profile for NASH treatment as evidenced by the hepato-protective and anti-steatotic effects observed in vivo. The preclinical characterization of EDP-305 presented here suggests that it holds promise for the treatment of NASH.

Covering the Cover

Covering the Cover

Nonacidic Farnesoid X Receptor Modulators.

As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.