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Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists

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Book cover Bile Acids and Their Receptors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 256))

Abstract

In the recent years, bile acid receptors FXR and GPBAR1 have attracted the interest of scientific community and companies, as they proved promising targets for the treatment of several diseases, ranging from liver cholestatic disorders to metabolic syndrome, inflammatory states, nonalcoholic steatohepatitis (NASH), and diabetes.

Consequently, the development of dual FXR/GPBAR1 agonists, as well as selective targeting of one of these receptors, is considered a hopeful possibility in the treatment of these disorders. Because endogenous bile acids and steroidal ligands, which cover the same chemical space of bile acids, often target both receptor families, speculation on nonsteroidal ligands represents a promising and innovative strategy to selectively target GPBAR1 or FXR.

In this review, we summarize the most recent acquisition on natural, semisynthetic, and synthetic steroidal and nonsteroidal ligands, able to interact with FXR and GPBAR1.

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Abbreviations

ANIT:

Alpha-naphthylisothiocyanate

BSEP:

Bile salt export pump

CDCA:

Chenodeoxycholic acid

DIO:

Diet-induced obesity

HFD:

High-fat diet

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

PBC:

Primary biliary cirrhosis

SHP:

Small heterodimer partner

UDCA:

Ursodeoxycholic acid

References

  • Abenavoli L, Capasso R, Milic N et al (2010) Milk thistle in liver diseases: past, present, future. Phytother Res 24:1423–1432

    Article  CAS  PubMed  Google Scholar 

  • Agarwal S, Patil A, Aware U et al (2016) Discovery of a potent and orally efficacious TGR5 receptor agonist. ACS Med Chem Lett 7:51–55

    Article  CAS  PubMed  Google Scholar 

  • Alemi F, Kwon E, Poole DP et al (2013) The TGR5 receptor mediates bile acid-induced itch and analgesia. J Clin Invest 123:1513–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biagioli M, Carino A, Cipriani S et al (2017) The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J Immunol 199:718–733

    Article  CAS  PubMed  Google Scholar 

  • Bijak M (2017) Silybin, a major bioactive component of Milk thistle (Silybum marianum L. Gaernt.) – chemistry, bioavailability, and metabolism. Molecules 22:1942–1952

    Article  PubMed Central  CAS  Google Scholar 

  • Budzik BW, Evans KA, Wisnoski DD et al (2010) Synthesis and structure-activity relationships of a series of 3-aryl-4-isoxazolecarboxamides as a new class of TGR5 agonists. Bioorg Med Chem Lett 20:1363–1367

    Article  CAS  PubMed  Google Scholar 

  • Burris TP, Montrose C, Houck KA et al (2005) The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand. Mol Pharmacol 67:948–954

    Article  CAS  PubMed  Google Scholar 

  • Cao H, Chen ZX, Wang K et al (2016) Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect. Sci Rep 6:28676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carino A, Graziosi L, D’Amore C et al (2016) The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines. Oncotarget 7:61021–61035

    Article  PubMed  PubMed Central  Google Scholar 

  • Carino A, Cipriani S, Marchianò S et al (2017a) BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep 7:42801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carino A, Cipriani S, Marchianò S et al (2017b) GPBAR1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice. Sci Rep 7:13689

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carino A, Biagioli M, Marchianò S et al (2018) Disruption of TFGβ-SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand. Pharmacol Res 131:17–31

    Article  CAS  PubMed  Google Scholar 

  • Carotti A, Marinozzi M, Custodi C et al (2014) Beyond bile acids: targeting farnesoid X receptor (FXR) with natural and synthetic ligands. Curr Top Med Chem 14:2129–2142

    Article  CAS  PubMed  Google Scholar 

  • Carter BA, Taylor OA, Prendergast DR et al (2007) Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res 62:301–306

    Article  CAS  PubMed  Google Scholar 

  • Chen T, Reich NW, Bell N et al (2018) Design of gut-restricted thiazolidine agonists of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5). J Med Chem 61:7589–7613

    Article  CAS  PubMed  Google Scholar 

  • Choi H, Hwang H, Chin J et al (2011) Tuberatolides, potent FXR antagonists from the Korean marine tunicate Botryllus tuberatus. J Nat Prod 74:90–94

    Article  CAS  PubMed  Google Scholar 

  • Cipriani S, Renga B, D’Amore C et al (2015) Impaired itching perception in murine models of cholestasis is supported by dysregulation of GPBAR1 signaling. PLoS One 10:e0129866

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Comeglio P, Morelli A, Adorini L et al (2017) Beneficial effects of bile acid receptor agonists in pulmonary disease models. Expert Opin Investig Drugs 26:1215–1228

    Article  CAS  PubMed  Google Scholar 

  • Comeglio P, Cellai I, Mello T et al (2018) INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function. J Endocrinol 238:107–127

    Article  CAS  PubMed  Google Scholar 

  • Crawley ML (2010) Farnesoid X receptor modulators: a patent review. Expert Opin Ther Pat 20:1047–1057

    Article  CAS  PubMed  Google Scholar 

  • Cui J, Huang L, Zhao A et al (2003) Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 278:10214–10220

    Article  CAS  PubMed  Google Scholar 

  • D’Amore C, Di Leva FS, Sepe V et al (2014) Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors. J Med Chem 57:937–954

    Article  PubMed  CAS  Google Scholar 

  • D’Auria MV, Sepe V, Zampella A (2012) Natural ligands for nuclear receptors: biology and potential therapeutic applications. Curr Top Med Chem 12:637–669

    Article  PubMed  Google Scholar 

  • Deng G, Li W, Shen J et al (2008) Pyrazolidine-3,5-dione derivatives as potent non-steroidal agonists of farnesoid X receptor: virtual screening, synthesis, and biological evaluation. Bioorg Med Chem Lett 18:5497–5502

    Article  CAS  PubMed  Google Scholar 

  • Deng YF, Hung XL, Su M et al (2018) Hypolipidemic effect of SIPI-7623, a derivative of an extract from oriental wormwood, through farnesoid X receptor antagonism. Chin J Nat Med 16:572–579

    PubMed  CAS  Google Scholar 

  • Di Leva FS, Festa C, D’Amore C et al (2013) Binding mechanism of the farnesoid X receptor marine antagonist suvanine reveals a strategy to forestall drug modulation on nuclear receptors. Design, synthesis, and biological evaluation of novel ligands. J Med Chem 56:4701–4717

    Article  PubMed  CAS  Google Scholar 

  • Diao Y, Jiang J, Zhang S et al (2018) Discovery of natural products as novel and potent FXR antagonists by virtual screening. Front Chem 6:140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Downes M, Verdecia MA, Roecker AJ et al (2003) Chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11:1079–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan H, Ning M, Zou Q et al (2015) Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. J Med Chem 58:3315–3328

    Article  CAS  PubMed  Google Scholar 

  • Epifano F, Genovese S, Squires EJ et al (2012) Nelumal A, the active principle from Ligulariane lumbifolia, is a novel farnesoid X receptor agonist. Bioorg Med Chem Lett 22:3130–3135

    Article  CAS  PubMed  Google Scholar 

  • Evans KA, Budzik BW, Ross SA et al (2009) Discovery of 3-aryl-4-isoxazolecarboxamides as TGR5 receptor agonists. J Med Chem 52:7962–7965

    Article  CAS  PubMed  Google Scholar 

  • Festa C, Renga B, D’Amore C et al (2014) Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands. J Med Chem 57:8477–8495

    Article  CAS  PubMed  Google Scholar 

  • Festa C, De Marino S, Carino A et al (2017) Targeting bile acid receptors: discovery of a potent and selective farnesoid X receptor agonist as a new lead in the pharmacological approach to liver diseases. Front Pharmacol 8:162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Festa C, Finamore C, Marchianò S et al (2019) Investigation around the oxadiazole core in the discovery of a new chemotype of potent and selective FXR antagonists. ACS Med Chem Lett 10:504–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiorucci S, Distrutti E, Bifulco G et al (2012) Marine sponge steroids as nuclear receptor ligands. Trends Pharmacol Sci 33:591–601

    Article  CAS  PubMed  Google Scholar 

  • Flatt B, Martin R, Wang TL et al (2009) Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem 52:904–907

    Article  CAS  PubMed  Google Scholar 

  • Flesch D, Gabler M, Lill A (2015) Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties. Bioorg Med Chem 23:3490–3498

    Article  CAS  PubMed  Google Scholar 

  • Gao X, Fu T, Wang C et al (2018) Yangonin protects against cholestasis and hepatotoxity via activation of farnesoid X receptor in vivo and in vitro. Toxicol Appl Pharmacol 348:105–116

    Article  CAS  PubMed  Google Scholar 

  • Genovese S, Epifano F (2011) Auraptene: a natural biologically active compound with multiple targets. Curr Drug Targets 12:381–386

    Article  CAS  PubMed  Google Scholar 

  • Giancristofaro A, Barbosa AJM, Ammazzalorso A (2018) Discovery of new FXR agonists based on 6-ECDCA binding properties by virtual screening and molecular docking. Med Chem Commun 9:1630–1638

    Article  CAS  Google Scholar 

  • Gilead Sciences (2016) Evaluating the safety, tolerability, and efficacy of GS-9674 in participants with nonalcoholic steatohepatitis (NASH). https://clinicaltrials.gov/ct2/show/NCT02854605

    Google Scholar 

  • Gioiello A, Macchiarulo A, Carotti A et al (2011) Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3alpha,7alpha-dihydroxy-6alpha-ethyl-24-nor-5beta-cholan-23-amine. Bioorg Med Chem 19:2650–2658

    Article  CAS  PubMed  Google Scholar 

  • Goldstein J, Levy C (2018) Novel and emerging therapies for cholestatic liver diseases. Liver Int 38:1520–1535

    Article  PubMed  Google Scholar 

  • Gu M, Zhao P, Huang J et al (2016) Silymarin ameliorates metabolic dysfunction associated with diet-induced obesity via activation of farnesyl X receptor. Front Pharmacol 7:345

    PubMed  PubMed Central  Google Scholar 

  • Gu M, Zhang S, Zhao Y et al (2017) Cycloastragenol improves hepatic steatosis by activating farnesoid X receptor signalling. Pharmacol Res 121:22–32

    Article  CAS  PubMed  Google Scholar 

  • Guo Z (2016) Artemisinin anti-malarial drugs in China. Acta Pharm Sin B 6:115–124

    Article  PubMed  PubMed Central  Google Scholar 

  • Herbert MR, Siegel DL, Staszewski L et al (2010) Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5. Bioorg Med Chem 20:5718–5721

    Article  CAS  Google Scholar 

  • Hodge RJ, Lin J, Vasist Johnson LS et al (2013) Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB-756050, in type 2 diabetes. Clin Pharmacol Drug Dev 2:213–222

    Article  CAS  PubMed  Google Scholar 

  • Horiba T, Katsukawa M, Mita M et al (2015) Dietary obacunone supplementation stimulates muscle hypertrophy, and suppresses hyperglycemia and obesity through the TGR5 and PPARγ pathway. Biochem Biophys Res Commun 463:846–852

    Article  CAS  PubMed  Google Scholar 

  • Hu XY, Guo YQ, Gao WY et al (2008) Two new triterpenes from the rhizomes of Alisma orientalis. J Asian Nat Prod Res 10:481–484

    Article  PubMed  CAS  Google Scholar 

  • Hu YB, Liu XY, Zhan W (2018) Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis. Drug Des Devel Ther 12:2213–2221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Yu Y, Gao Z et al (2012) Discovery and optimization of 1,3,4-trisubstitutedpyrazolonederivatives as novel, potent, and nonsteroidal farnesoid X receptor (FXR) selective antagonists. J Med Chem 55:7037–7053

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Xu Y, Zhu J et al (2014) Recent advances in non-steroidal FXR antagonists development for therapeutic applications. Curr Top Med Chem 14:2175–2187

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Si P, Wang L et al (2015) Design, synthesis, and biological evaluation of novel nonsteroidal farnesoid X receptor (FXR) antagonists: molecular basis of FXR antagonism. ChemMedChem 10:1184–1199

    Article  CAS  PubMed  Google Scholar 

  • Iracheta-Vellve A, Calenda CD, Petrasek J et al (2018) FXR and TGR5 agonists ameliorate liver injury, steatosis, and inflammation after binge or prolonged alcohol feeding in mice. Hepatol Commun 2:1379–1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jadhav K, Xu Y, Xu Y et al (2018) Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR. Mol Metab 9:131–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinzel O, Steeneck C, Schlüter T et al (2016) Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: understanding and improving key determinants of pharmacological properties. Bioorg Med Chem Lett 26:3746–3753

    Article  CAS  PubMed  Google Scholar 

  • Kirchweger B, Kratz JM, Ladurner A et al (2018) In silico workflow for the discovery of natural products activating the G protein-coupled bile acid receptor 1. Front Chem 6:242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kumar DP, Rajagopal S, Mahavadi S et al (2012) Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells. Biochem Biophys Res Commun 427:600–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar DP, Asgharpour A, Mirshahi F et al (2016) Activation of transmembrane bile acid receptor TGR5 modulates pancreatic islet α cells to promote glucose homeostasis. J Biol Chem 291:6626–6640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuroyanagi K, Kang MS, Goto T et al (2008) Citrus auraptene acts as an agonist for PPARs and enhances adiponectin production and MCP-1 reduction in 3T3-L1 adipocytes. Biochem Biophys Res Commun 366:219–225

    Article  CAS  PubMed  Google Scholar 

  • Ladurner A, Zehl M, Grienke U et al (2017) All spice and clove as source of triterpene acids activating the G protein-coupled bile acid receptor TGR5. Front Pharmacol 8:468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lasalle M, Hoguet V, Hennuyer N et al (2017) Topical intestinal aminoimidazole agonists of G-protein-coupled bile acid receptor 1 promote glucagon like peptide-1 secretion and improve glucose tolerance. J Med Chem 60:4185–4211

    Article  CAS  PubMed  Google Scholar 

  • Li L, Hou X, Xu R et al (2017) Research review on the pharmacological effects of astragaloside IV. Fundam Clin Pharmacol 31:17–36

    Article  CAS  PubMed  Google Scholar 

  • Lin HR (2012) Triterpenes from Alisma orientalis act as farnesoid X receptor agonists. Bioorg Med Chem 22:4787–4792

    Article  CAS  Google Scholar 

  • Lin HR (2015) Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist. J Asian Nat Prod Res 17:149–158

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Law W, Wang D et al (2014a) Synthesis and discovery of andrographolide derivatives as non-steroidal farnesoid X receptor (FXR) antagonists. RSC Adv 4:13533–13545

    Article  CAS  Google Scholar 

  • Liu P, Xu X, Chen L et al (2014b) Discovery and SAR study of hydroxyacetophenone derivatives as potent, non-steroidal farnesoid X receptor (FXR) antagonists. Bioorg Med Chem 22:1596–1607

    Article  CAS  PubMed  Google Scholar 

  • Lo SH, Cheng KC, Li YX et al (2016) Development of betulinic acid as an agonist of TGR5 receptor using a new in vitro assay. Drug Des Devel Ther 10:2669–2676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lo SH, Li Y, Cheng KC et al (2017) Ursolic acid activates the TGR5 receptor to enhance GLP-1 secretion in type 1-like diabetic rats. Naunyn Schmiedeberg’s Arch Pharmacol 390:1097–1104

    Article  CAS  Google Scholar 

  • Lu Y, Zheng W, Lin S et al (2018) Identification of an oleanane-type triterpene hedragonic acid as a novel farnesoid X receptor ligand with liver protective effects and anti-inflammatory activity. Mol Pharmacol 93:63–72

    Article  CAS  PubMed  Google Scholar 

  • Ma SY, Ning MM, Zou QA et al (2016) OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition. Acta Pharmacol Sin 37:1359–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1136

    Article  CAS  PubMed  Google Scholar 

  • Maloney PR, Parks DJ, Haffner CD et al (2000) Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43:2971–2974

    Article  CAS  PubMed  Google Scholar 

  • Maruyama T, Miyamoto Y, Nakamura T et al (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719

    Article  CAS  PubMed  Google Scholar 

  • Mason A, Luketic V, Lindor K et al (2010) Farnesoid-X receptor agonists: a new class of drugs for the treatment of PBC? An international study evaluating the addition of INT-747 to ursodeoxycholic acid. J Hepatol 52:S1–S2

    Article  Google Scholar 

  • Mehlmann JF, Crawley ML, Lundquist JT IV et al (2009) Pyrrole[2,3-d]azepino compounds as agonists of the farnesoid X receptor (FXR). Bioorg Med Chem Lett 19:5289–5292

    Article  CAS  PubMed  Google Scholar 

  • Meng Q, Chen X, Wang C et al (2014) Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor. Biochem Pharmacol 92:289–298

    Article  CAS  PubMed  Google Scholar 

  • Meng Q, Chen X, Wang C et al (2015) Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis. Toxicol Appl Pharmacol 283:178–186

    Article  CAS  PubMed  Google Scholar 

  • Meng Q, Duan X, Wang C et al (2017) Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation. Acta Pharmacol Sin 38:69–79

    Article  CAS  PubMed  Google Scholar 

  • Merk D, Steinhilber D, Schubert-Zsilavecz M (2012) Medicinal chemistry of farnesoid X receptor ligands: from agonists and antagonists to modulators. Future Med Chem 4:1015–1036

    Article  CAS  PubMed  Google Scholar 

  • Merk D, Gabler M, Gomez RC et al (2014a) Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR). Bioorg Med Chem Lett 22:2447–2460

    Article  CAS  Google Scholar 

  • Merk D, Lamers C, Ahmad K et al (2014b) Extending the structure-activity relationship of anthranilic acid derivatives as farnesoid X receptor modulators: development of a highly potent partial farnesoid X receptor agonist. J Med Chem 57:8035–8055

    Article  CAS  PubMed  Google Scholar 

  • Moris D, Giaginis C, Tsourouflis G et al (2017) Farnesoid-X receptor (FXR) as a promising pharmaceutical target in atherosclerosis. Curr Med Chem 24:1147–1157

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi S, Toki S, Saitoh Y et al (1995) Isolation of myosin light chain kinase inhibitors from microorganisms: dehydroaltenusin, altenusin, atrovenetinone, and cyclooctasulfur. Biosci Biotechnol Biochem 59:1333–1335

    Article  CAS  PubMed  Google Scholar 

  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965

    Article  CAS  PubMed  Google Scholar 

  • Novartis Pharmaceuticals (2015) A multipart, double blind study to assess safety, tolerability and efficacy of LJN452 in PBC patients. https://clinicaltrials.gov/ct2/show/NCT02516605

    Google Scholar 

  • Novartis Pharmaceuticals (2016) Study of safety and efficacy of tropifexor (LJN452) in patients with non-alcoholic steatohepatitis (NASH) (FLIGHT-FXR). https://clinicaltrials.gov/ct2/show/NCT02855164

    Google Scholar 

  • Nozawa H (2005) Xanthohumol, the chalcone from beer hops (Humulus lupulus L.), is the ligand for farnesoid X receptor and ameliorates lipid and glucose metabolism in KK-A(y) mice. Biochem Biophys Res Commun 336:754–761

    Article  CAS  PubMed  Google Scholar 

  • Ono E, Inoue J, Hashidume T et al (2011) Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet. Biochem Biophys Res Commun 410:677–681

    Article  CAS  PubMed  Google Scholar 

  • Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368

    Article  CAS  PubMed  Google Scholar 

  • Pellicciari R, Fiorucci S, Camaioni E et al (2002) 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 45:3569–3572

    Article  CAS  PubMed  Google Scholar 

  • Pellicciari R, Gioiello A, Sabbatini P et al (2012) Avicholic acid: a lead compound from birds on the route to potent TGR5 modulators. ACS Med Chem Lett 3:273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pellicciari R, Passeri D, De Franco F et al (2016) Discovery of 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100), a novel bile acid as potent and highly selective FXR agonist for enterohepatic disorders. J Med Chem 9:9201–9214

    Article  CAS  Google Scholar 

  • Peng GP, Tian G, Huang XF et al (2003) Guaiane-type sesquiterpenoids from Alisma orientalis. Phytochemistry 63:877–881

    Article  CAS  PubMed  Google Scholar 

  • Phenex Pharmaceuticals AG (2011) Single ascending oral dose phase I study with Px-102. https://clinicaltrials.gov/ct2/show/NCT01998659

    Google Scholar 

  • Phenex Pharmaceuticals AG (2012) Multiple ascending oral dose phase I study with Px-102. Responsible. https://clinicaltrials.gov/ct2/show/NCT01998672

    Google Scholar 

  • Phenex Pharmaceuticals AG (2013) Safety pilot study of farnesoid X receptor (FXR) agonist in non-alcoholic fatty liver disease (NAFLD) patients. https://clinicaltrials.gov/ct2/show/NCT01999101

    Google Scholar 

  • Pols TWH, Nomura M, Harach T et al (2011) TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 14:747–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Putra MY, Bavestrello G, Cerrano C et al (2012) Polyhydroxylated sterols from the Indonesian soft coral Sinularia sp. and their effect on farnesoid X-activated receptor. Steroids 77:433–440

    Article  CAS  PubMed  Google Scholar 

  • Renga B, Mencarelli A, D’Amore C, Cipriani S, D’Auria MV, Sepe V, Chini MG, Monti MC, Bifulco G, Zampella A, Fiorucci F (2012) Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis. PLoS One 7:e30443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richter HG, Benson GM, Bleicher KH et al (2011a) Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties. Bioorg Med Chem Lett 21:1134–1140

    Article  CAS  PubMed  Google Scholar 

  • Richter HG, Benson GM, Blum D et al (2011b) Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia and diabetes. Bioorg Med Chem Lett 21:191–194

    Article  CAS  PubMed  Google Scholar 

  • Rizzo G, Passeri D, De Franco F et al (2010) Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol 78:617–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roth JD, Feigh M, Veidal SS et al (2018) INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J Gastroenterol 24:195–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sato S, Genet C, Strehle A et al (2007) Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem Biophys Res Commun 362:793–798

    Article  CAS  PubMed  Google Scholar 

  • Schmidt J, Schierle S, Gellrich L et al (2018) Structural optimization and in vitro profiling of N-phenylbenzamide-based farnesoid X receptor antagonists. Bioorg Med Chem 26:4240–4253

    Article  CAS  PubMed  Google Scholar 

  • Schwabl P, Hambruch E, Seeland BA et al (2017) The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 66:724–733

    Article  CAS  PubMed  Google Scholar 

  • Sepe V, Ummarino R, D’Auria MV et al (2012) Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei. Mar Drugs 10:2448–2466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sepe V, Distrutti E, Limongelli V et al (2015a) Steroidal scaffolds as FXR and GPBAR1 ligands: from chemistry to therapeutical application. Future Med Chem 7:1109–1135

    Article  CAS  PubMed  Google Scholar 

  • Sepe V, Distrutti E, Fiorucci S et al (2015b) Farnesoid X receptor modulators (2011–2014): a patent review. Expert Opin Ther Pat 25:885–896

    Article  CAS  PubMed  Google Scholar 

  • Sepe V, Festa C, Renga B et al (2016a) Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists. Sci Rep 6:19008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sepe V, Renga B, Festa C et al (2016b) Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity. Steroids 105:59–67

    Article  CAS  PubMed  Google Scholar 

  • Sepe V, Distrutti E, Fiorucci S et al (2018) Farnesoid X receptor modulators 2014-present: a patent review. Expert Opin Ther Pat 28:351–364

    Article  CAS  PubMed  Google Scholar 

  • Sepe V, Machiarnò S, Finamore C et al (2019) Novel isoxazole derivatives with potent FXR agonistic activity prevent acetaminophen-induced liver injury. ACS Med Chem Lett. https://doi.org/10.1021/acsmedchemlett.8b00423

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sindhu T, Srinivasan P (2014) Pharmacophore modeling, 3D-QSAR and molecular docking studies of benzimidazole derivatives as potential FXR agonists. J Recept Signal Transduct Res 34:241–253

    Article  CAS  PubMed  Google Scholar 

  • Song K, Xu X, Liu P et al (2015) Discovery and SAR study of 3-(tert-butyl)-4-hydroxyphenyl benzoate and benzamide derivatives as novel farnesoid X receptor (FXR) antagonists. Bioorg Med Chem 23:6427–6436

    Article  CAS  PubMed  Google Scholar 

  • Takahashi N, Kang MS, Kuroyanagi K et al (2008) Auraptene, a citrus fruit compound, regulates gene expression as a PPARα agonist in HepG2 hepatocytes. Biofactors 33:25–32

    Article  CAS  PubMed  Google Scholar 

  • Teno N, Yamashita Y, Iguchi Y et al (2018) Nonacidic chemotype possessing N-acylatedpiperidine moiety as potent farnesoid X receptor (FXR) antagonists. ACS Med Chem Lett 9:78–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas C, Gioiello A, Noriega L et al (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10:167–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai CJ, Liang JW, Lin HR (2012) Sesquiterpenoids from Atractylodes macrocephala act as farnesoid X receptor and progesterone receptor modulators. Bioorg Med Chem Lett 22:2326–2329

    Article  CAS  PubMed  Google Scholar 

  • Tully DC, Rucker PV, Chianelli D et al (2017) Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem 60:9960–9973

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Chen J, Hollister K et al (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Zhang JX, Shen XL et al (2004) Reversal of P-glycoprotein-mediated multidrug resistance by alisol B 23-acetate. Biochem Pharmacol 68:843–855

    Article  CAS  PubMed  Google Scholar 

  • Wang LY, Cheng KC, Li Y et al (2017a) Glycyrrhizic acid increases glucagon like peptide-1 secretion via TGR5 activation in type 1-like diabetic rats. Biomed Pharmacother 95:599–604

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Zhao Z, Zhou J et al (2017b) A novel intestinal-restricted FXR agonist. Bioorg Med Chem Lett 27:3386–3390

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Xia C, Meier J et al (2002) The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor. Mol Endocrinol 16:1590–1597

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Yang-Ge Lv YG, Du YF et al (2019) Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. Prog Neuropsychopharmacol Biol Psychiatry 88:360–374

    Article  CAS  PubMed  Google Scholar 

  • Wua X, Lv YG, Du YF et al (2018) Neuroprotective effects of INT-777 against Aβ1–42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. Brain Behav Immun 73:533–545

    Article  CAS  Google Scholar 

  • Xiao H, Li P, Li X et al (2017) Synthesis and biological evaluation of a series of bile acid derivatives as FXR agonists for treatment of NASH. ACS Med Chem Lett 8:1246–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y (2016) Recent progress on bile acid receptor modulators for treatment of metabolic diseases. J Med Chem 59:6553–6579

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Xu X, Liu P et al (2015) Structural basis for small molecule NDB (N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide) as a selective antagonist of farnesoid X receptor α (FXRα) in stabilizing the homodimerization of the receptor. J Biol Chem 290:19888–19899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu W, Lu C, Yao L et al (2017) Dihydroartemisinin protects against alcoholic liver injury through alleviating hepatocyte steatosis in a farnesoid X receptor-dependent manner. Toxicol Appl Pharmacol 315:23–34

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Broderick D, Campbell Y et al (2016) Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies. Biochim Biophys Acta 1864:1667–1677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu DD, Lin W, Forman BM et al (2014) Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor. Bioorg Med Chem 22:2919–2938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu DD, Sousa KM, Mattern DL et al (2015) Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists. Bioorg Med Chem 23:1613–1628

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Wall M, Sui Z et al (2017) Discovery of orally efficacious tetrahydrobenzimidazoles as TGR5 agonists for type 2 diabetes. ACS Med Chem Lett 8:560–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng T, Kim NY, Yim M (2017a) Fexaramine inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast formation via nuclear factor of activated T cells signaling pathways. J Bone Metab 24:207–215

    Article  PubMed  PubMed Central  Google Scholar 

  • Zheng W, Lu Y, Lin S et al (2017b) A novel class of natural FXR modulators with a unique mode of selective co-regulator assembly. ChemBioChem 18:721–725

    Article  CAS  PubMed  Google Scholar 

  • Zheng Z, Zhao Z, Li S et al (2017c) Altenusin, a nonsteroidal microbial metabolite, attenuates nonalcoholic fatty liver disease by activating the farnesoid X receptor. Mol Pharmacol 92:425–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, University of Naples “Federico II”, Naples, Italy

    Simona De Marino, Carmen Festa, Valentina Sepe & Angela Zampella

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  1. Simona De Marino
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  2. Carmen Festa
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  3. Valentina Sepe
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  4. Angela Zampella
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Correspondence to Angela Zampella .

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  1. University of Perugia, School of Medicine, Perugia, Italy

    Stefano Fiorucci

  2. S.C. Gastroenterologia, Azienda Ospedaliera di Perugia, Perugia, Italy

    Eleonora Distrutti

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De Marino, S., Festa, C., Sepe, V., Zampella, A. (2019). Chemistry and Pharmacology of GPBAR1 and FXR Selective Agonists, Dual Agonists, and Antagonists. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_237

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