166
Views
2
CrossRef citations to date
0
Altmetric
Review

Patented Farnesoid X receptor modulators: a review (2019 – present)

, &
Pages 547-564 | Received 10 Nov 2023, Accepted 25 Jan 2024, Published online: 26 Feb 2024

References

  • Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol. 2021;18(5):335–347. doi: 10.1038/s41575-020-00404-2
  • Massafra V, van Mil SWC. Farnesoid X receptor: a “homeostat” for hepatic nutrient metabolism. Biochim Biophys Acta Mol Basis Dis. 2018;1864(1):45–49. doi: 10.1016/j.bbadis.2017.10.003
  • Massafra V, Pellicciari R, Gioiello A, et al. Progress and challenges of selective farnesoid X receptor modulation. Pharmacol Ther. 2018;191:162–177. doi: 10.1016/j.pharmthera.2018.06.009
  • Huber RM, Murphy K, Miao B, et al. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene. 2002;290(1–2):35–43. doi: 10.1016/S0378-1119(02)00557-7
  • Zhang Y, Kast-Woelbern HR, Edwards PA. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem. 2003;278(1):104–110. doi: 10.1074/jbc.M209505200
  • Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284(5418):1362–1365. doi: 10.1126/science.284.5418.1362
  • Gadaleta RM, Cariello M, Sabbà C, et al. Tissue-specific actions of FXR in metabolism and cancer. Biochim Biophys Acta. 2015;1851(1):30–39. doi: 10.1016/j.bbalip.2014.08.005
  • Inagaki T, Choi M, Moschetta A, et al. L. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005;2(4):217–225. doi: 10.1016/j.cmet.2005.09.001
  • Kim I, Ahn SH, Inagaki T, et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007;48(12):2664–2672. doi: 10.1194/jlr.M700330-JLR200
  • Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16(1):459–481. doi: 10.1146/annurev.cellbio.16.1.459
  • Gadaleta RM, Scialpi N, Peres C, et al. Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis. Sci Rep. 2018;8(1):17210. doi: 10.1038/s41598-018-35496-z
  • Ridlon JM, Alves JM, Hylemon PB, et al. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes. 2013;4(5):382–387. doi: 10.4161/gmic.25723
  • Gadaleta RM, van Erpecum KJ, Oldenburg B, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut. 2011;60(4):463–472. doi: 10.1136/gut.2010.212159
  • Patti ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity. 2009;17(9):1671–1677. doi: 10.1038/oby.2009.102
  • Sun L, Xie C, Wang G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018;24(12):1919–1929. doi: 10.1038/s41591-018-0222-4
  • Zhang L, Xie C, Nochols RG, et al. Farnesoid x receptor signaling shapes the gut microbiota and controls hepatic lipid metabolism. mSystems. 2016;1(5):e00070–e00076. doi: 10.1128/mSystems.00070-16
  • Jiang C, Xie C, Li F, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest. 2015;125(1):386–402. doi: 10.1172/JCI76738
  • Jiang C, Xie C, Lv Y, et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun. 2015;6(1):10166. doi: 10.1038/ncomms10166
  • Hui S, Liu Y, Chen M, et al. Capsaicin improves glucose tolerance and insulin sensitivity through modulation of the gut microbiota-bile acid-FXR axis in type 2 diabetic db/db mice. Mol Nutrition Food Res. 2019;63(23):e1900608. doi: 10.1002/mnfr.201900608
  • Xu X, Shi X, Chen Y, et al. HS218 as an FXR antagonist suppresses gluconeogenesis by inhibiting FXR binding to PGC-1a promoter. Metabolism. 2018;85:126–138. doi: 10.1016/j.metabol.2018.03.016
  • Renga B, Mencarelli A, D’Amore C, et al. Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis. PLoS One. 2012;7(1):e30443. doi: 10.1371/journal.pone.0030443
  • Vavassori P, Mencarelli A, Renga B, et al. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol. 2009;183(10):6251–6261. doi: 10.4049/jimmunol.0803978
  • Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(4):751–761.e8. doi: 10.1053/j.gastro.2014.12.005
  • Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2018;67(5):1890–1902. doi: 10.1002/hep.29569
  • Clinical trial: safety, tolerability, pharmacokinetics and efficacy of LMB763 in patients with NASH (NCT02913105). [cited 2023 Oct 27]. Available from: https://classic.clinicaltrials.gov/ct2/show/results/NCT02913105.
  • Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2014;385(9972):956–965. doi: 10.1016/S0140-6736(14)61933-4
  • Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid x receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574–582.e1. doi: 10.1053/j.gastro.2013.05.042
  • Panzitt K, Zollner G, Marschall HU, et al. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol. 2022;552:111678. doi: 10.1016/j.mce.2022.111678
  • Zeng J, Fan J, Zhou H. Bile acid-mediated signaling in cholestatic liver diseases. Cell Biosci. 2023;13(1):77. doi: 10.1186/s13578-023-01035-1
  • Pellicciari R, Pruzanski M, Gioiello A. The discovery of obeticholic acid (Ocaliva™): first-in-class FXR agonist. In: Fischer J, Klein C, and Childers WE, editors. Successful drug discovery. Vol. 3. Wiley-VCH Verlag GmbH & Co. KGaA; 2018. p. 197–244. doi: 10.1002/9783527808694.ch8
  • Clinical trial: study of INT-747 as monotherapy in participants with primary biliary cirrhosis (PBC) (NCT00570765). [cited 2023 Oct 27]. Available from: https://clinicaltrials.gov/study/NCT00570765.
  • Clinical trial: study of INT 747 in combination with urso in patients with primary biliary cirrhosis (PBC) (NCT00550862). [cited 2023 Oct 27]. Available from: https://clinicaltrials.gov/study/NCT00550862.
  • Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45(17):3569–3572. doi: 10.1021/jm025529g
  • Li Y, Roqueta-Rivera M, Garlick K, et al. Characterization of EDP-305, a highly potent and selective Farnesoid X receptor agonist, for the treatment of non-alcoholic steatohepatitis. IJG. 2019;3(1):4–16. doi: 10.11648/j.ijg.20190301.12
  • Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol. 2023;79(5):1317–1331.
  • Tully DC, Rucker PV, Chianelli D, et al. 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. 2017;60(24):9960–9973. doi: 10.1021/acs.jmedchem.7b00907
  • Trauner M, Gulamhusein A, Hameed B, et al. The nonsteroidal Farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatol. 2019;70(3):788–801. doi: 10.1002/hep.30509
  • Genin MJ, Bueno AB, Agejas FJ, et al. Discovery of 6-(4-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid: a novel FXR agonist for the treatment of dyslipidemia. J Med Chem. 2015;58(24):9768–9772. doi: 10.1021/acs.jmedchem.5b01161
  • Chianelli D, Rucker PV, Roland J, et al. Nidufexor (LMB763), a novel FXR modulator for the treatment of nonalcoholic steatohepatitis. J Med Chem. 2020;63(8):3868–3880. doi: 10.1021/acs.jmedchem.9b01621
  • Wagner B, Govek S, Nagasawa J, et al. MET409, a potent, novel, non-bile acid FXR agonist, in rodents and cynomolgus monkeys. Hepatol. 2017;68:1049A.
  • Darteil R, Joly S, Radreau P, et al. In vitro characterization of Eyp001 a novel, potent and selective FXR agonist entering phase 2 clinical trials in chronic hepatitis B. Hepatol. 2019;70. Abstract 87.
  • [cited 2023 Oct 27]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/166997176
  • Karlsen TH, Folseraas T, Thorburn D, et al. Primary sclerosing cholangitis – a comprehensive review. J Hepatol. 2017;67(6):1298–1323. doi: 10.1016/j.jhep.2017.07.022
  • Lindor KD, Kowdley KV, Harrison ME. ACG clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol. 2015;110(5):646–659. doi: 10.1038/ajg.2015.112
  • Levy C, Hejda V, Louvet A, et al. Combined effect of obeticholic acid and bezafibrate in patients with primary biliary cholangitis and inadequate response to or intolerance of ursodeoxycholic acid: results from two clinical trials. Late breaking abstract at: the Liver Meeting 2023; Nov 13, 2023; Boston, MA. Abstract 5019.
  • Jiang L, Zhang H, Xiao D, et al. Farnesoid X receptor (FXR): Structures and ligands. Comput Struct Biotechnol J. 2021;19:2148–2159. doi: 10.1016/j.csbj.2021.04.029
  • Sepe V, Distrutti E, Fiorucci S, et al. Farnesoid X receptor modulators 2014-present: a patent review. Expert Opin Ther Pat. 2018;28(5):351–364. doi: 10.1080/13543776.2018.1459569
  • Gioiello A, Cerra B, Mostarda S, et al. Bile acid derivatives as ligands of the Farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation. CTMC. 2014;14(19):2159–2174. doi: 10.2174/1568026614666141112100208
  • Carotti A, Marinozzi M, Custodi C, et al. Beyond bile acids: targeting Farnesoid x receptor (FXR) with natural and synthetic ligands. CTMC. 2014;14(19):2129–2142. doi: 10.2174/1568026614666141112094058
  • Fang Y, Hegazy L, Finck BN, et al. Recent advances in the medicinal chemistry of farnesoid x receptor. J Med Chem. 2021;64(24):17545–17571. doi: 10.1021/acs.jmedchem.1c01017
  • Roda A, Pellicciari R, Gioiello A, et al. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat. J Pharmacol Exp Ther. 2014;350(1):56–68. doi: 10.1124/jpet.114.214650
  • Pellicciari R, Gioiello A, Sabbatini P, et al. Avicholic acid: a lead compound from birds on the route to potent TGR5 modulators. ACS Med Chem Lett. 2012;3(4):273–277. doi: 10.1021/ml200256d
  • Fujino T, Une M, Imanaka T, et al. Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation. J Lipid Res. 2004;45(1):132–138. doi: 10.1194/jlr.M300215-JLR200
  • Pellicciari R, Passeri D, De Franco F, et al. 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. 2016;59(19):9201–9214. doi: 10.1021/acs.jmedchem.6b01126.
  • Di Pasqua LG, Cagna M, Palladini G, et al. FXR agonists INT-787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet-induced ob/ob mouse model of NASH. Liver Int. 2024;44(1):214–227. doi: 10.1111/liv.15767
  • Marzano M, Fosso B, Colliva C, et al. Farnesoid X receptor activation by the novel agonist TC-100 (3α, 7α, 11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid) preserves the intestinal barrier integrity and promotes intestinal microbial reshaping in a mouse model of obstructed bile acid flow. Biomed Pharmacother. 2022;153:113380. doi: 10.1016/j.biopha.2022.113380
  • Intercept Pharmaceuticals Inc. Farnesoid x receptor modulators. US11034717 (granted patent). 2021.
  • Xiao H, Li P, Li X, et al. Synthesis and biological evaluation of a series of bile acid derivatives as FXR agonists for treatment of NASH. ACS Med Chem Lett. 2017;8(12):1246–1251. doi: 10.1021/acsmedchemlett.7b00318
  • Pellicciari R, Costantino G, Camaioni E, et al. 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. J Med Chem. 2004;47(18):4559–4569. doi: 10.1021/jm049904b
  • Rizzo G, Passeri D, De Franco F, et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol Pharmacol. 2010;78(4):617–630. doi: 10.1124/mol.110.064501
  • Festa C, Renga B, D’Amore C, et al. 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. 2017;57(20):8477–8495. doi: 10.1021/jm501273r
  • Pellicciari R, Gioiello A, Costantino G, et al. Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives. J Med Chem. 2006;49(14):4208–4215. doi: 10.1021/jm060294k
  • Rosatelli E, Carotti A, Cerra B, et al. Chemical exploration of TGR5 functional hot-spots: synthesis and structure-activity relationships of C7- and C23-substituted cholic acid derivatives. Eur J Med Chem. 2023;261:115851. doi: 10.1016/j.ejmech.2023.115851
  • Wang X, Qiu L, Hazra S, et al. Dual activation of FXR and TGR5 protects from diabetic nephropathy and retinopathy in mouse model of type 1 diabetes. American Diabetes Association (ADA) 73rd Scientific Sessions, Jun 21-25, 2013; Chicago, Illinois.
  • Baghdasaryan A, Claudel T, Gumhold J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2 −/− (Abcb4 −/−) mouse cholangiopathy model by promoting biliary HCO 3− output. Hepatology. 2011;54(4):1303–1312. doi: 10.1002/hep.24537
  • Comeglio P, Cellai I, Mello T, et al. INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function. J Endocrinol. 2018;238(2):107–127. doi: 10.1530/JOE-17-0557
  • Hu YB, Liu XY, Zhan W. Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis. Drug Design Dev Ther. 2018;12:2213–2221. doi: 10.2147/DDDT.S170518
  • Clinical trial: safety, tolerability, pharmacokinetics, and pharmacodynamics of BAR 502 in healthy subjects (NCT 05203367). [cited 2023 Oct 27]. Available from: https://clinicaltrials.gov/study/NCT05203367.
  • Carino A, Cipriani S, Marchianò S, et al. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep. 2017;7(1):42801. doi: 10.1038/srep42801
  • Gioiello A, Macchiarulo A, Carotti A, et al. Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine. Bioorg Med Chem. 2011;19(8):2650–2658. doi: 10.1016/j.bmc.2011.03.004
  • Wen’anluo Institute, Shanghai Institute of Materia Medica of CAS. Cholic acid derivatives and its preparation method and application. CN110343140 (application). 2019.
  • The regents of the University of California. Bile acids and use in disease treatment. WO2020154397 (application). 2020.
  • Enanta Pharmaceuticals Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof. US11040998 (granted patent). 2021.
  • Zhenjiang Shengan Pharmaceutical Co ltd and Jiangsu Jibeier Pharmaceutical Co ltd. Tauroursodeoxycholic acid derivative, and pharmaceutical composition and preparation comprising same. CN112142814 (granted patent). 2021.
  • Intercept Pharmaceuticals Inc. 3-desoxy derivative and pharmaceutical compositions thereof. US11319337B2 (granted patent, 2022).
  • Mi LZ, Devarakonda S, Harp JM, et al. tructural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell. 2003;11:1093–1110. doi: 10.1016/s1097-2765(03)00112-6
  • Nzp Uk Ltd, University of Southampton. Fluorinated bile acid derivatives. US11517577 (granted patent). 2022.
  • Hepaitech (Beijing) Biopharma Technology. Polycyclic compounds and methods thereof. WO2023083343A1 (application). 2023.
  • Meixiong J, Vasavda C, Snyder SH, et al. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus. PNAS. 2019;116(21):10525–10530. doi: 10.1073/pnas.1903316116
  • Peng W, Ni H, Guo D, et al. Farnesoid X receptor regulators from natural products and their biological function. J Tradit Chin Med. 2023;43(3):618–626. doi: 10.19852/j.cnki.jtcm.20230404.002
  • She J, Gu T, Pang X, et al. Natural products targeting Liver X receptors or Farnesoid X receptor. Front Pharmacol. 2022;12:772435. doi: 10.3389/fphar.2021.772435
  • Shanghai Institute of Materia Medica of CAS. Pentacyclic triterpenoid and preparation method, pharmaceutical composition and application thereof. CN109517022 (granted patent, 2022).
  • Yale University. Methods of inducing or enhancing farnesoid x receptor (fxr)-mediated transcriptional response. WO2021102124 (application, 2020).
  • Xiang JM, Zhong GY, Jiang W, et al. [Analysis of varieties and standards of Saxifragaceae medicinal plants used in Tibetan medicine]. Zhongguo Zhong Yao Za Zhi. 2021;46(2):488–493. doi: 10.19540/j.cnki.cjcmm.20200902.601
  • Jiangxi University of Traditional Chinese Medicine. Oleanane-type triterpenic acid and composition thereof, and preparation method and application thereof. CN114057825 (application, 2021).
  • Shanghai Institute of Materia Medica of CAS. Tricyclic FXR receptor antagonist and preparation method thereof. CN115504880 (application, 2021).
  • Maloney PR, Parks DJ, Haffner CD, et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem. 2000;43(16):2971–2974. doi: 10.1021/jm0002127
  • Kinzel O, Steeneck C, Schlüter T, et al. Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: understanding and improving key determinants of pharmacological properties. Bioorg Med Chem Lett. 2016;26(15):3746–3753. doi: 10.1016/j.bmcl.2016.05.070
  • Downes M, Verdecia MA, Roecker AJ, et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell. 2003;11(4):1079–1092. doi: 10.1016/S1097-2765(03)00104-7
  • Nicolau KC, Evans RM, Roecker AJ, et al. Discovery and optimization of non-steroidal FXR agonists from natural product-like libraries. Org Biomol Chem. 2003;1(6):908–920. doi: 10.1039/b300525a
  • Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21(2):159–165. doi: 10.1038/nm.3760
  • Metacrine, Inc. Farnesoid x receptor agonists and uses thereof. WO2020061113 (application, 2020).
  • Metacrine, Inc. Farnesoid x receptor agonists for the treatment of disease. WO2021188688 (application, 2021).
  • Bristol Myers Squibb Co. Substituted amide compounds useful as farnesoid x receptor modulators. US20220213026 (application, 2020).
  • Bristol Myers Squibb Co. Substituted bicyclic compounds as farnesoid X receptor modulators. US11254663 (granted patent, 2022).
  • Bar Pharmaceuticals, S.r.l. Oxadiazoles as fxr receptor antagonists. WO2019224743 (application, 2019).
  • Henan University. Application of benzbromarone as FXR agonist. CN111265511 (application, 2020).
  • Poxel. Pharmaceutical combination of a specific thienopyridone derivative with an fxr agonist for the treatment of liver diseases. WO2021037702 (application, 2021).
  • Clinical trial: study to assess the safety, tolerability, and pharmacokinetics of PXL770 in healthy subjects (NCT05441904). [cited 2023 Oct 27]. https://classic.clinicaltrials.gov/ct2/show/NCT05441904.
  • Enanta Pharmaceuticals Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof. US10208081 (granted patent, 2019).
  • Enanta Pharmaceuticals Inc. Process for preparation of sulfonylurea bile acid derivatives. US10584145 (granted patent, 2020).
  • Phenex Pharmaceuticals Ag. Novel fxr (nr1h4) binding and activity modulating compounds. WO2013007387 (application, 2013).
  • Gilead Sciences Inc. FXR (NR1H4) binding and activity modulating compounds. US9139539 (granted patent, 2015).
  • Sichuan Kelun Biotech Biopharmaceutical Co Ltd. Preparation method of compound serving as farnesoid X receptor agonist. CN 115215853 (application, 2022).
  • Passeri D, Carotti A, Ramos Pittol JM, et al. Dissecting the allosteric FXR modulation: a chemical biology approach using guggulsterone as a chemical tool. MedChemcommun. 2019;10(8):1412–1419. doi: 10.1039/C9MD00264B
  • Bijsmans I, Guercini C, Ramos Pittol JM, et al. The glucocorticoid mometasone furoate is a novel FXR ligand that decreases inflammatory but not metabolic gene expression. Sci Rep. 2015;5(1):14086. doi: 10.1038/srep14086
  • Merk D, Sreeramulu S, Kudklinzki D, et al. Molecular tuning of farnesoid X receptor partial agonism. Nat Commun. 2019;10(1):1–14. doi: 10.1038/s41467-019-10853-2.
  • Helmstädter M, Kaiser A, Brunst S, et al. Second-generation dual FXR/sEH modulators with optimized pharmacokinetics. J Med Chem. 2021;64(13):9525–9536. doi: 10.1021/acs.jmedchem.1c00831
  • Schierle S, Brunst S, Helmstädter M, et al. Development and in vitro profiling of dual FXR/LTA4H modulators. ChemMedchem. 2021;16(15):2366. doi: 10.1002/cmdc.202100118
  • Jonker JW, Liddle C, Downes M. FXR and PXR: potential therapeutic targets in cholestasis. J Steroid Biochem Mol Biol. 2012;130(3–5):147–158. doi: 10.1016/j.jsbmb.2011.06.012
  • Zhou S, You H, Qiu S, et al. A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Biomed Pharmacother. 2022;154:113577. doi: 10.1016/j.biopha.2022.113577
  • Ren Q, Chen Y, Zhou Z, et al. Discovery of the first-in-class intestinal restricted FXR and FABP1 dual modulator ZLY28 for the treatment of nonalcoholic fatty liver disease. J Med Chem. 2023;66(9):6082–6104. doi: 10.1021/acs.jmedchem.2c01918
  • Chen Y, Song X, Valanejad L, et al. Bile salt export pump is dysregulated with altered farnesoid X receptor isoform expression in patients with hepatocellular carcinoma. Hepatol. 2013;57(4):1530–1541. doi: 10.1002/hep.26187

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.