{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:59:49Z","timestamp":1780466389647,"version":"3.54.1"},"reference-count":39,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["84173118"],"award-info":[{"award-number":["84173118"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["2021-I2M-1-028"],"award-info":[{"award-number":["2021-I2M-1-028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["2018ZX09711001-001-001"],"award-info":[{"award-number":["2018ZX09711001-001-001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["2018ZX09711001-001-003"],"award-info":[{"award-number":["2018ZX09711001-001-003"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS)","award":["84173118"],"award-info":[{"award-number":["84173118"]}]},{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS)","award":["2021-I2M-1-028"],"award-info":[{"award-number":["2021-I2M-1-028"]}]},{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS)","award":["2018ZX09711001-001-001"],"award-info":[{"award-number":["2018ZX09711001-001-001"]}]},{"name":"CAMS Innovation Fund for Medical Sciences (CIFMS)","award":["2018ZX09711001-001-003"],"award-info":[{"award-number":["2018ZX09711001-001-003"]}]},{"name":"National Key New Drug Creation and Manufacturing Program","award":["84173118"],"award-info":[{"award-number":["84173118"]}]},{"name":"National Key New Drug Creation and Manufacturing Program","award":["2021-I2M-1-028"],"award-info":[{"award-number":["2021-I2M-1-028"]}]},{"name":"National Key New Drug Creation and Manufacturing Program","award":["2018ZX09711001-001-001"],"award-info":[{"award-number":["2018ZX09711001-001-001"]}]},{"name":"National Key New Drug Creation and Manufacturing Program","award":["2018ZX09711001-001-003"],"award-info":[{"award-number":["2018ZX09711001-001-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12\u03b2-O-(\u03b3-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure\u2013activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg\u00b7Kg\u22121) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11\u2013H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12\u03b2-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH).<\/jats:p>","DOI":"10.3390\/ph16050758","type":"journal-article","created":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T07:35:50Z","timestamp":1684395350000},"page":"758","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structure Optimization of 12\u03b2-O-\u03b3-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist\/Modulator for NASH Therapy"],"prefix":"10.3390","volume":"16","author":[{"given":"Hao","family":"Ma","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyang","family":"Bao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaishuai","family":"Niu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaorong","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9159-091X","authenticated-orcid":false,"given":"Hongwei","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weishuo","family":"Fang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nan Wei Road, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.1093\/nar\/gkg444","article-title":"The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily","volume":"31","author":"Maglich","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41575-020-00404-2","article-title":"The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer","volume":"18","author":"Sun","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1016\/j.csbj.2021.04.029","article-title":"Farnesoid X receptor (FXR): Structures and ligands","volume":"19","author":"Jiang","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mori, H., Svegliati Baroni, G., Marzioni, M., Di Nicola, F., Santori, P., Maroni, L., Abenavoli, L., and Scarpellini, E. (2022). Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota. Metabolites, 12.","DOI":"10.3390\/metabo12070647"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/164_2019_226","article-title":"Chenodeoxycholic Acid: An Update on Its Therapeutic Applications","volume":"256","author":"Fiorucci","year":"2019","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1021\/jm025529g","article-title":"6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity","volume":"45","author":"Pellicciari","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Floreani, A., Gabbia, D., and De Martin, S. (2022). Obeticholic Acid for Primary Biliary Cholangitis. Biomedicines, 10.","DOI":"10.3390\/biomedicines10102464"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e0005","DOI":"10.1097\/HC9.0000000000000005","article-title":"Safety and tolerability of obeticholic acid in chronic liver disease: A pooled analysis of 1878 individuals","volume":"7","author":"Ng","year":"2023","journal-title":"Hepatol. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Renga, B., Mencarelli, A., D\u2019Amore, C., Cipriani, S., D\u2019Auria, M.V., Sepe, V., Chini, M.G., Monti, M.C., Bifulco, G., and Zampella, A. (2012). Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030443"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Deuschle, U., Schuler, J., Schulz, A., Schluter, T., Kinzel, O., Abel, U., and Kremoser, C. (2012). FXR controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an orthotopic mouse xenograft model. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043044"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S1665-2681(19)31949-0","article-title":"Biliary secretion and excretion in health and disease: Current concepts","volume":"6","author":"Hofmann","year":"2007","journal-title":"Ann. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1073\/pnas.0506982103","article-title":"Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice","volume":"103","author":"Zhang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1194\/jlr.M070888","article-title":"Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters","volume":"58","author":"Dong","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"154771","DOI":"10.1016\/j.metabol.2021.154771","article-title":"Mebhydrolin ameliorates glucose homeostasis in type 2 diabetic mice by functioning as a selective FXR antagonist","volume":"119","author":"Zhao","year":"2021","journal-title":"Metabolism"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1021\/acsmedchemlett.8b00534","article-title":"Investigation around the Oxadiazole Core in the Discovery of a New Chemotype of Potent and Selective FXR Antagonists","volume":"10","author":"Festa","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112910","DOI":"10.1016\/j.ejmech.2020.112910","article-title":"Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator","volume":"209","author":"Luo","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.pharmthera.2018.06.009","article-title":"Progress and challenges of selective Farnesoid X Receptor modulation","volume":"191","author":"Massafra","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1177\/0960327118817862","article-title":"Guggulsterone, a farnesoid X receptor antagonist lowers plasma trimethylamine-N-oxide levels: An evidence from in vitro and in vivo studies","volume":"38","author":"Gautam","year":"2019","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106203","DOI":"10.1016\/j.bioorg.2022.106203","article-title":"Discovery of 12beta-oxygenated oleanolic acid alkyl esters as potent and selective FXR modulators exhibiting hyperglycemia amelioration in vivo","volume":"129","author":"Wang","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Leo, R., Therachiyil, L., Siveen, S.K., Uddin, S., Kulinski, M., Buddenkotte, J., Steinhoff, M., and Krishnankutty, A.R. (2019). Protein Expression Profiling Identifies Key Proteins and Pathways Involved in Growth Inhibitory Effects Exerted by Guggulsterone in Human Colorectal Cancer Cells. Cancers, 11.","DOI":"10.3390\/cancers11101478"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"313","DOI":"10.37349\/etat.2020.00019","article-title":"Potential of guggulsterone, a farnesoid X receptor antagonist, in the prevention and treatment of cancer","volume":"1","author":"Girisa","year":"2020","journal-title":"Explor. Target. Antitumor Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1021\/jm0582221","article-title":"Farnesoid X receptor: From structure to potential clinical applications","volume":"48","author":"Pellicciari","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1126\/science.1072891","article-title":"A natural product that lowers cholesterol as an antagonist ligand for FXR","volume":"296","author":"Urizar","year":"2002","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"294","DOI":"10.2174\/1381612822666151112153117","article-title":"Guggulsterone for Chemoprevention of Cancer","volume":"22","author":"Shishodia","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.2042-7158.2010.01158.x","article-title":"Preclinical pharmacokinetics, dose proportionality, gender difference and protein binding study of 16-dehydropregnenolone, an antihyperlipidemic agent, in rats","volume":"63","author":"Suryawanshi","year":"2011","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1038\/ncomms2924","article-title":"The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism","volume":"4","author":"Jin","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1002\/ptr.2948","article-title":"Oleanolic acid is a selective farnesoid X receptor modulator","volume":"24","author":"Liu","year":"2010","journal-title":"Phytother. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.jep.2005.05.024","article-title":"Oleanolic acid and ursolic acid: Research perspectives","volume":"100","author":"Liu","year":"2005","journal-title":"J. Ethnopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1152\/physrev.00049.2019","article-title":"Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging","volume":"101","author":"Perino","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5466","DOI":"10.1111\/1750-3841.15951","article-title":"Policosanol alleviates hepatic lipid accumulation by regulating bile acids metabolism in C57BL6\/mice through AMPK-FXR-TGR5 cross-talk","volume":"86","author":"Zhai","year":"2021","journal-title":"J. Food Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1038\/s41467-019-10853-2","article-title":"Molecular tuning of farnesoid X receptor partial agonism","volume":"10","author":"Merk","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2174\/157016307781483469","article-title":"Current treatment strategies for non-alcoholic fatty liver disease (NAFLD)","volume":"4","author":"Mishra","year":"2007","journal-title":"Curr. Drug. Discov. Technol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1053\/j.gastro.2020.01.043","article-title":"Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis","volume":"158","author":"Taylor","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Han, C.Y. (2018). Update on FXR Biology: Promising Therapeutic Target?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072069"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1124\/jpet.108.144600","article-title":"Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet","volume":"328","author":"Kong","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S0140-6736(14)61933-4","article-title":"Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial","volume":"385","author":"Loomba","year":"2015","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1111\/bph.14570","article-title":"Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice","volume":"176","author":"Gu","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"771976","DOI":"10.3389\/fphar.2021.771976","article-title":"Ilexsaponin A(1) Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice","volume":"12","author":"Zhao","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Eichhorn, T., Kolbe, F., Misic, S., Dimic, D., Morgan, I., Saoud, M., Milenkovic, D., Markovic, Z., Ruffer, T., and Dimitric Markovic, J. (2022). Synthesis, Crystallographic Structure, Theoretical Analysis, Molecular Docking Studies, and Biological Activity Evaluation of Binuclear Ru(II)-1-Naphthylhydrazine Complex. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010689"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/5\/758\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:37:03Z","timestamp":1760125023000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/5\/758"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,17]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ph16050758"],"URL":"https:\/\/doi.org\/10.3390\/ph16050758","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,17]]}}}