Bile Acid Derivatives as Ligands of the Farnesoid X Receptor. Synthesis, Evaluation, and Structure−Activity Relationship of a Series of Body and Side Chain Modified Analogues of Chenodeoxycholic Acid

Pellicciari, Roberto; Costantino, Gabriele; Camaioni, Emidio; Sadeghpour, Bahman M.; Entrena, Antonio; Willson, Timothy M.; Fiorucci, Stefano; Clerici, Carlo; Gioiello, Antimo

doi:10.1021/jm049904b

Cited by 168 publications

(114 citation statements)

References 41 publications

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“…Pharmacological activation of FXR was obtained by in vivo and in vitro treatment with 6-ethyl-CDCA (INT-747), a semisynthetic FXR ligand that activates the receptor with an EC 50 of Ϸ 100 nM (21)(22)(23). The efficacy of INT-747 was tested in acute and chronic models of colon inflammation induced by trinitrobenzenesulfonic acid (TNBS) or dextran sulfate (DSS) (24,25).…”

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

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The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

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526

442

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The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR−/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

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Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

“…TNBS colitis was induced by intrarectal administration of TNBS (0.5 mg/mouse) in 50% ethanol (21,22). Mice receiving TNBS were randomized to receive no treatment or INT-747 at a dose of 5 mg/kg (n ϭ 10 for each group).…”

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

Self Cite

526

442

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“…In addition to their role in bile acid homeostasis, FXRs have been found to regulate liver regeneration during liver injury (33)(34)(35)(36)(37)(38). Obeticholic acid (OCA, INT-747), a 6-ethyl derivative of the natural human bile acid chenodeoxycholic acid (CDCA), is a first-in-class selective FXR agonist with ~ 100-fold greater FXR agonistic activity than CDCA (39)(40)(41). In a male Wistar rat model of cholestasis, OCA protected hepatocytes against deleterious effects caused by administration of lithocholic acid (LCA) (41).…”

Section: Farnesoid X Receptor Agonists and Pscmentioning

confidence: 99%

Current research on the treatment of primary sclerosing cholangitis

Ali

Carey

Lindor

2015

IRDR

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“…Two major patterns of modification were elaborated around the BA scaffold, namely, those affecting the B ring of the steroid nucleus and those relating to the side chain [15][16][17][18][19][20][21][22][23]. These studies have revealed that even minor modifications designed to obtain a desired biological activity, can also significantly affect the physico-chemical properties, metabolic behaviour, distribution within different districts and tissues, and, most importantly, the cytotoxicity profile of the new analogues with respect to the parent natural BA [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

“…Based on these considerations and following our interest in BA research [15,16,[18][19][20][21][22], in this paper, we investigate the effect of BA side chain modifications with respect to their capacity to generate micelles. In particular, we report the synthesis, CMC evaluation and structure-property considerations of a series of hyodeoxycholic acid (HDCA) derivatives characterized by a different side chain length and by the presence of a methyl group at the alpha position of the carboxylic acid tail (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Quantitative Structure-Property Relationships of Side Chain-Modified Hyodeoxycholic Acid Derivatives

Sabbatini¹,

Filipponi

Sardella

et al. 2013

Molecules

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Bile acids have emerged as versatile signalling compounds of a complex network of nuclear and membrane receptors regulating various endocrine and paracrine functions. The elucidation of the interconnection between the biological pathways under the bile acid control and manifestations of hepatic and metabolic diseases have extended the scope of this class of steroids for in vivo investigations. In this framework, the design and synthesis of novel biliary derivatives able to modulate a specific receptor requires a deep understanding of both structure-activity and structure-property relationships of bile acids. In this paper, we report the preparation and the critical micellization concentration evaluation of a series of hyodeoxycholic acid derivatives characterized by a diverse side chain length and by the presence of a methyl group at the alpha position with respect to the terminal carboxylic acid moiety. The data collected are instrumental to extend on a quantitative basis, the knowledge of the current structure-property relationships of bile acids and will be fruitful, in combination with models of receptor activity, to design and prioritize the synthesis of novel pharmacokinetically suitable ligands useful in the validation of bile acid-responsive receptors as therapeutic targets.

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Bile Acid Derivatives as Ligands of the Farnesoid X Receptor. Synthesis, Evaluation, and Structure−Activity Relationship of a Series of Body and Side Chain Modified Analogues of Chenodeoxycholic Acid

Cited by 168 publications

References 41 publications

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Current research on the treatment of primary sclerosing cholangitis

Synthesis and Quantitative Structure-Property Relationships of Side Chain-Modified Hyodeoxycholic Acid Derivatives

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