Fexaramine

Fexaramine is a small molecule farnesoid X receptor (FXR) agonist with 100-fold increased affinity relative to natural compounds. IC50 value: Target: in vitro: In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter [1]. Fexaramine significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced extracellular signal-regulated kinase (ERK) and β-catenin signaling [2]. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver [3].

References:
[1]. Lam IP, et al. Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP). Am J Physiol Gastrointest Liver Physiol. 2009 Jul;297(1):G90-7. [2]. Cho SW, et al. Positive regulation of osteogenesis by bile acid through FXR. J Bone Miner Res. 2013 Oct;28(10):2109-21. [3]. Fang S, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015 Feb;21(2):159-65.

Fexaramine as an entry blocker for feline caliciviruses.[Pubmed:29454892]

Antiviral Res. 2018 Apr;152:76-83.

Feline calicivirus (FCV) is a small non-enveloped virus containing a single-stranded, positive-sense RNA genome of approximately 7.7kb. FCV is a highly infectious pathogen of cats and typically causes moderate, self-limiting acute oral and upper respiratory tract diseases or chronic oral diseases. In addition, in recent years, virulent, systemic FCV (vs-FCV) strains causing severe systemic diseases with a high mortality rate of up to 67% have been reported in cats. Although FCV vaccines are commercially available, their efficacy is limited due to antigenic diversity of FCV strains and short duration of immunity. In this study, we identified Fexaramine as a potent inhibitor of FCV including vs-FCV strains in cell culture and demonstrated that Fexaramine is a entry blocker for FCV by using various experiments including time-of-addition studies, generation of resistant viruses in cell culture and the reverse genetics system. A Fexaramine resistant FCV mutant has a single amino acid change in the P2 domain of VP1 (the major capsid), and the importance of this mutation for conferring resistance was confirmed using the reverse genetics system. A comparative analysis of viral resistance was also performed using a peptidyl inhibitor (NPI52) targeting FCV 3C-like protease. Finally, the effects of combination treatment of Fexaramine and NPI52 against FCV replication and emergence of resistant viruses were investigated in cell culture.

Fexaramine Inhibits Receptor Activator of Nuclear Factor-kappaB Ligand-induced Osteoclast Formation via Nuclear Factor of Activated T Cells Signaling Pathways.[Pubmed:29259959]

J Bone Metab. 2017 Nov;24(4):207-215.

Background: Osteoclasts are bone resorbing cells and are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Fexaramine has been developed as an agonist for the farnesoid X receptor (FXR). This study investigated the effects of Fexaramine on receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-induced osteoclast formation and signaling pathways. Methods: Osteoclasts were formed by culturing mouse bone marrow-derived macrophages (BMMs) with macrophage colony-stimulating factor (M-CSF) and RANKL. Bone resorption assays were performed using dentine slices. The mRNA expression level was analyzed by real-time polymerase chain reaction. Western blotting assays were conducted to detect the expression or activation level of proteins. Lipopolysaccharide-induced osteoclast formation was performed using a mouse calvarial model. Results: Fexaramine inhibited RANKL-induced osteoclast formation, without cytotoxicity. Furthermore, Fexaramine diminished the RANKL-stimulated bone resorption. Mechanistically, Fexaramine blocked the RANKL-triggered p38, extracellular signal-regulated kinase, and glycogen synthase kinase 3beta phosphorylation, resulting in suppressed expression of c-Fos and NF of activated T cells (NFATc1). Consistent with the in vitro anti-osteoclastogenic effect, Fexaramine suppressed lipopolysaccharide-induced osteoclast formation in the calvarial model. Conclusions: The present data suggest that Fexaramine has an inhibitory effect on osteoclast differentiation and function, via downregulation of NFATc1 signaling pathways. Thus, Fexaramine could be useful for the treatment of bone diseases associated with excessive bone resorption.

Positive regulation of osteogenesis by bile acid through FXR.[Pubmed:23609136]

J Bone Miner Res. 2013 Oct;28(10):2109-21.

Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid sensor controlling bile acid homeostasis. We investigated the role of FXR in regulating bone metabolism. We identified the expression of FXR in calvaria and bone marrow cells, which gradually increased during osteoblastic differentiation in vitro. In male mice, deletion of FXR (FXR(-/-) ) in vivo resulted in a significant reduction in bone mineral density by 4.3% to 6.6% in mice 8 to 20 weeks of age compared with FXR(+/+) mice. Histological analysis of the lumbar spine showed that FXR deficiency reduced the bone formation rate as well as the trabecular bone volume and thickness. Moreover, tartrate-resistant acid phosphatase (TRACP) staining of the femurs revealed that both the osteoclast number and osteoclast surface were significantly increased in FXR(-/-) mice compared with FXR(+/+) mice. At the cellular level, induction of alkaline phosphatase (ALP) activities was blunted in primary calvarial cells in FXR(-/-) mice compared with FXR(+/+) mice in concert with a significant reduction in type I collagen a1(Col1a1), ALP, and runt-related transcription factor 2 (Runx2) gene expressions. Cultures of bone marrow-derived macrophages from FXR(-/-) mice exhibited an increased number of osteoclast formations and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In female FXR(-/-) mice, although bone mineral density (BMD) was not significantly different from that in FXR(+/+) mice, bone loss was accelerated after an ovariectomy compared with FXR(+/+) mice. In vitro, activation of FXR by bile acids (chenodeoxycholic acid [CDCA] or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced extracellular signal-regulated kinase (ERK) and beta-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol (FOH 1%) diet marginally prevented ovariectomy (OVX)-induced bone loss and enhanced bone mass gain in growing C57BL/6J mice. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of the bone remodeling pathways; ie, bone formation and resorption.

Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.[Pubmed:16821780]

J Med Chem. 2006 Jul 13;49(14):4208-15.

Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the carboxylic tail opposite the transactivation function 2 (AF-2, helix 12), functionalization of the side chain is not expected to interfere directly with the orientation of H12 but can result in a more indirect way of receptor modulation. The newly synthesized compounds were extensively characterized for their ability to modulate FXR function in a variety of assays, including the cell-free fluorescence resonance energy transfer (FRET) assay and the cell-based luciferase transactivation assay, and displayed a broad range of activity from full agonism to partial antagonism. Docking studies clearly indicate that the side chain of the new derivatives fits in a so far unexploited receptor cavity localized near the "back door" of FXR. We thus demonstrate the possibility of achieving a broad FXR modulation without directly affecting the H12 orientation.

A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.[Pubmed:12718892]

Mol Cell. 2003 Apr;11(4):1079-92.

The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed Fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific Fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of Fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of Fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases.

Discovery and optimization of non-steroidal FXR agonists from natural product-like libraries.[Pubmed:12929628]

Org Biomol Chem. 2003 Mar 21;1(6):908-20.

The efficient regulation of cholesterol biosynthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. Herein, we describe the development of four novel classes of potent FXR activators originating from natural product-like libraries. Initial screening of a 10,000-membered, diversity-orientated library of benzopyran containing small molecules for FXR activation utilizing a cell-based reporter assay led to the identification of several lead compounds possessing low micromolar activity (EC50's = 5-10 microM). These compounds were systematically optimized employing parallel solution-phase synthesis and solid-phase synthesis to provide four classes of compounds that potently activate FXR. Two series of compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds may find future utility as chemical tools in studies aimed at further defining the physiological role of FXR and discovering potential therapeutic agents for the treatment of diseases linked to cholesterol and bile acid metabolism and homeostasis.

Fexaramine is a small molecule farnesoid X receptor (FXR) agonist with 100-fold increased affinity relative to natural compounds.

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