Discovery of FXR/PPARγ dual partial agonist

Yukiko Yamashita; Keigo Gohda; Yusuke Iguchi; Ko Fujimori; Keisuke Oda; Arisa Masuda; Mizuho Une; Naoki Teno

doi:10.1016/j.bmc.2023.117238

journal article May 01, 2023

Discovery of FXR/PPARγ dual partial agonist

Yukiko Yamashita Keigo Gohda Yusuke Iguchi Ko Fujimori Keisuke Oda Arisa Masuda Mizuho Une Naoki Teno

Bioorganic & Medicinal Chemistry Vol. 85 pp. 117238 · Elsevier BV

View at Publisher Save 10.1016/j.bmc.2023.117238

Topics

No keywords indexed for this article. Browse by subject →

References

53

[1]

Identification of a Nuclear Receptor for Bile Acids

Makoto Makishima, Arthur Y. Okamoto, Joyce J. Repa et al.

Science 1999 10.1126/science.284.5418.1362

[2]

Bile Acids: Natural Ligands for an Orphan Nuclear Receptor

Derek J. Parks, Steven G. Blanchard, Randy K. Bledsoe et al.

Science 1999 10.1126/science.284.5418.1365

[3]

Armstrong "Role of FXR in liver inflammation during nonalcoholic steatohepatitis" Curr Pharmacol Rep. (2017) 10.1007/s40495-017-0085-2

[4]

Farnesoid X receptor is essential for normal glucose homeostasis

K. Ma

Journal of Clinical Investigation 2006 10.1172/jci25604

[5]

Sinal "Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis" Cell (2000) 10.1016/s0092-8674(00)00062-3

[6]

Goodwin "A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis" Mol Cell. (2000) 10.1016/s1097-2765(00)00051-4

[7]

Uriarte "Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice" Gut (2013) 10.1136/gutjnl-2012-302945

[8]

Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Mitsuhiro Watanabe, Sander M. Houten, Li Wang et al.

Journal of Clinical Investigation 2004 10.1172/jci21025

[9]

SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis

Jiyu Zhou, Shuang Cui, Qingxian He et al.

Nature Communications 2020 10.1038/s41467-019-14138-6

[10]

Bowlus "Obeticholic Acid for the Treatment of Primary Biliary Cholangitis in Adult Patients: Clinical Utility and Patient Selection" Hepatic Med. (2016) 10.2147/hmer.s91709

[11]

Neuschwander-Tetri "X. nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial" Lancet (2015) 10.1016/s0140-6736(14)61933-4

[12]

Tully "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) 10.1021/acs.jmedchem.7b00907

[13]

Younossi "Obeticholic acid for the treatment of non-alcoholic steatohepatitis: Interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial" Lancet (2019) 10.1016/s0140-6736(19)33041-7

[14]

Pencek "Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers" Diabetes Obes Metabol. (2016) 10.1111/dom.12681

[15]

Genin "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) 10.1021/acs.jmedchem.5b01161

[16]

Maloney "Identification of a chemical tool for the orphan nuclear receptor FXR" J Med Chem. (2000) 10.1021/jm0002127

[17]

Akwabi-Ameyaw "Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064" Bioorg Med Chem Lett. (2008) 10.1016/j.bmcl.2008.06.073

[18]

Bass "Substituted Isoxazole Analogs of Farnesoid X Receptor (FXR) Agonist GW4064" Bioorg Med Chem Lett. (2009) 10.1016/j.bmcl.2009.04.047

[19]

https://www.clinicaltrialsarena.com/features/pipeline-moves-novartis-assets/.

[20]

Merk "Molecular tuning of farnesoid X receptor partial agonism" Nat Commun. (2019) 10.1038/s41467-019-10853-2

[21]

Aranda "Nuclear hormone receptors and gene expression" Physiol Rev. (2001) 10.1152/physrev.2001.81.3.1269

[22]

Rastinejad "Nuclear receptor full-length architectures: Confronting myth and illusion with high resolution" Trends Biochem Sci. (2015) 10.1016/j.tibs.2014.10.011

[23]

Barot "Novel research strategies of benzimidazole derivatives: A review" Mini Rev Med Chem. (2013) 10.2174/13895575113139990072

[24]

Bansal "The therapeutic journey of benzimidazoles: A review" Bioorg Med Chem. (2012) 10.1016/j.bmc.2012.09.013

[25]

Teno "Nonacidic chemotype possessing N-acylated piperidine moiety as potent farnesoid X receptor (FXR) antagonists" ACS Med Chem Lett. (2018) 10.1021/acsmedchemlett.7b00363

[26]

Teno "Discovery of orally active and nonsteroidal farnesoid X receptor (FXR) antagonist with propensity for accumulation and responsiveness in ileum" ACS Med Chem Lett. (2021) 10.1021/acsmedchemlett.0c00640

[27]

Masuda "N1-Substituted benzimidazole scaffold for farnesoid X receptor (FXR) agonists accompanying prominent selectivity against vitamin D receptor (VDR)" Bioorg Med Chem. (2020) 10.1016/j.bmc.2020.115512

[28]

Xie "Quinoxaline-2,3-diones: potential D-amino acid oxidase (DAAO) inhibitors" Med Chem Res. (2014) 10.1007/s00044-014-1068-z

[29]

Ueda "Trichlorophenyl formate: Highly reactive and easily accessible crystalline CO surrogate for palladium-catalyzed carbonylation of aryl/alkenyl halides and triflates" Org Lett. (2012) 10.1021/ol302593z

[30]

AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading

Oleg Trott, Arthur J. Olson

Journal of Computational Chemistry 2010 10.1002/jcc.21334

[31]

Rosen "C/EBPα induces adipogenesis through PPARγ: A unified pathway" Genes Dev. (2002) 10.1101/gad.948702

[32]

Maeda "PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein" Diabetes (2001) 10.2337/diabetes.50.9.2094

[33]

Ferguson "Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus" Nat Rev Endocrinol. (2021) 10.1038/s41574-021-00507-z

[34]

A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

Jennifer L. Oberfield, Jon L. Collins, Christopher P. Holmes et al.

Proceedings of the National Academy of Sciences 1999 10.1073/pnas.96.11.6102

[35]

Gurnell "The metabolic syndrome: Peroxisome proliferator-activated receptor and its therapeutic modulation" J Clin Endocrinol Metab. (2003) 10.1210/jc.2003-030435

[36]

Bruning "Partial agonists activate PPAR using a helix 12 independent mechanism" Structure (2007) 10.1016/j.str.2007.07.014

[37]

Meier "Use of thiazolidinediones and fracture risk" Arch Intern Med. (2008) 10.1001/archinte.168.8.820

[38]

Schwartz "TZDs and bone: A review of the recent clinical evidence" PPAR Res. (2008) 10.1155/2008/297893

[39]

Choi "Obesity-linked phosphorylation of PPARγ by Cdk5 is a direct target of the anti-diabetic PPARγ ligands" Nature (2010) 10.1038/nature09291

[40]

Choi "Antidiabetic actions of a non-agonist PPAR ligand blocking Cdk5-mediated phosphorylation" Nature (2011) 10.1038/nature10383

[41]

Henke "N-(2-Benzoylphenyl)-L-tyrosine PPAR agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents" J Med Chem. (1998) 10.1021/jm9804127

[42]

Gavin "Discovery by virtual screening of an inhibitor of CDK5-mediated PPARγ phosphorylation" ACS Med Chem Lett. (2022) 10.1021/acsmedchemlett.1c00715

[43]

Miyata "Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists" Sci Rep. (2021) 10.1038/s41598-021-88493-0

[44]

Schierle "Design and structural optimization of dual FXR/PPARδ activators" J Med Chem. (2020) 10.1021/acs.jmedchem.0c00618

[45]

Helmstädter "Second-generation dual FXR/sEH modulators with optimized Pharmacokinetics" J Med Chem. (2021) 10.1021/acs.jmedchem.1c00831

[46]

Belfort "A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis" N Eng J Med. (2006) 10.1056/nejmoa060326

[47]

Hamaguchi "The metabolic syndrome as a predictor of nanalcoholic fatty liver disease" Ann Intern Med. (2005) 10.7326/0003-4819-143-10-200511150-00009

[48]

The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases

Naga Chalasani, Zobair Younossi, Joel E. Lavine et al.

Hepatology 2018 10.1002/hep.29367

[49]

Younossi "Epidemiology of chronic liver diseases in the USA in the past three decades" Gut (2020) 10.1136/gutjnl-2019-318813

[50]

Targher "The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments" Nat Rev Gastroenterol Hepatol. (2021) 10.1038/s41575-021-00448-y

Showing 50 of 53 references

Cited By

11

Discovery of 7-ether substituted homoisoflavonoids as selective FXR modulators attenuating MASH via the FXR and AMPK pathways

Guoning Zhang, Wenqiang Jia · 2026

European Journal of Medicinal Chemi...

Metrics

11

Citations

53

References

Details

Published: May 01, 2023
Vol/Issue: 85
Pages: 117238
License: View

Authors

Cite This Article

Yukiko Yamashita, Keigo Gohda, Yusuke Iguchi, et al. (2023). Discovery of FXR/PPARγ dual partial agonist. Bioorganic & Medicinal Chemistry, 85, 117238. https://doi.org/10.1016/j.bmc.2023.117238

Discovery of FXR/PPARγ dual partial agonist

You May Also Like