Skip to main content
SpringerLink
Log in

Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 μM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 μM) and guggulsterone (IC50 = 45.9 ± 1.1 μM). Docking of A-11 in FXR’s ligand-binding domain was also studied.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

FXR:

Farnesoid X receptor

LBD:

Ligand-binding domain

GS:

Guggulsterone

TC:

Total cholesterol

TG:

Triacylglycerol

LDL-C:

Low-density lipoprotein cholesterol

References

  1. Jin J, Sun X, Zhao Z, Wang W, Qiu Y, Fu X, Huang M, Huang Z (2015) Activation of the farnesoid X receptor attenuates triptolide-induced liver toxicity. Phytomedicine 22:894–901. https://doi.org/10.1016/j.phymed.2015.06.007

    Article  CAS  PubMed  Google Scholar 

  2. Yang L, Broderick D, Campbell Y, Gombart AF, Stevens JF, Jiang Y, Hsu VL, Bisson WH, Maier CS (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. https://doi.org/10.1016/j.bbapap.2016.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gioiello A, Cerra B, Mostarda S, Guercini C, Pellicciari R, Macchiarulo A (2014) Bile acid derivatives as ligands of the farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation. Curr Top Med Chem 14:2159–2574. https://doi.org/10.2174/1568026614666141112100208

    Article  CAS  PubMed  Google Scholar 

  4. Song K, Xu X, Liu P, Chen L, Shen X, Liu J, Hu L (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. https://doi.org/10.1016/j.bmc.2015.08.021

    Article  CAS  PubMed  Google Scholar 

  5. Gioiello A, Cerra B, Mostarda S, Guercini C, Pellicciari R, Macchiarulo A (2014) Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands. Curr Top Med Chem 14:2129–2142. https://doi.org/10.2174/1568026614666141112094058

    Article  CAS  PubMed  Google Scholar 

  6. Huang H, Yu Y, Gao Z, Zhang Y, Li C, Xu X, Jin H, Yan W, Ma R, Zhu J, Shen X, Jiang H, Chen L, Li J (2012) Discovery and optimization of 1,3,4-trisubstituted-pyrazolone derivatives as novel, potent, and nonsteroidal farnesoid X receptor (FXR) selective antagonists. J Med Chem 55:7037–7053. https://doi.org/10.1021/jm3002718

    Article  CAS  PubMed  Google Scholar 

  7. Xu X, Xu X, Liu P, Zhu ZY, Chen J, Fu HA, Chen LL, Hu LH, Shen X (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. https://doi.org/10.1074/jbc.M114.630475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huang H, Xu Y, Zhu J, Li J (2014) Recent advances in non-steroidal FXR antagonists development for therapeutic applications. Curr Top Med Chem 14:2175–2187. https://doi.org/10.2174/1568026614666141112101840

    Article  CAS  PubMed  Google Scholar 

  9. Lamers C, Schubert-Zsilavecz M, Merk D (2014) Medicinal chemistry and pharmacological effects of farnesoid X receptor (FXR) antagonists. Curr Top Med Chem 14:2188–2205. https://doi.org/10.2174/1568026614666141112103516

    Article  CAS  PubMed  Google Scholar 

  10. Bellale E, Naik MVBV, Ambady A, Narayan A, Ravishankar S, Ramachandran V, Kaur P, McLaughlin R, Whiteaker J, Morayya S, Guptha S, Sharma S, Raichurkar A, Awasthy D, Achar V, Vachaspati P, Bandodkar B, Panda M, Chatterji M (2014) Diarylthiazole: an antimycobacterial scaffold potentially targeting PrrB-PrrA two-component system. J Med Chem 57:6572–6682. https://doi.org/10.1021/jm500833f

    Article  CAS  PubMed  Google Scholar 

  11. Maitrani C, Heyes DJ, Hay S, Arumugam S, Popik VV, Phillips RS (2012) Preparation and photophysical properties of a caged kynurenine. Bioorg Med Chem Lett 22:2734–2737. https://doi.org/10.1016/j.bmcl.2012.02.097

    Article  CAS  PubMed  Google Scholar 

  12. Uddin MJ, Elleman AV, Ghebreselasie K, Daniel CK, Crews BC, Nance KD, Huda T, Marnett LJ (2014) Design of fluorine-containing 3,4-diarylfuran-2(5H)-ones as selective COX-1 Inhibitors. ACS Med Chem Lett 5:1254–1258. https://doi.org/10.1021/ml500344j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McKervey MA, O’Sullivan MB, Myers PL (1993) Reductive acylation of α-keto azides derived from l-amino acids using N-protected l-aminothiocarboxylic s-acids. J Chem Soc Chem Commun 1:94–96. https://doi.org/10.1002/chin.199317106

    Article  Google Scholar 

  14. Atta AK, Kim SB, Cho DG (2011) Catalytic oxidative conversion of aldehydes to carboxylic esters and acids under mild conditions. Bull Korean Chem Soc 32:2070–2072. https://doi.org/10.5012/bkcs.2011.32.6.2070

    Article  CAS  Google Scholar 

  15. LaDow JE, Warnock DC, Hamill KM, Simmons KL, Davis RW, Schwantes CR, Flaherty DC, Willcox JA, Wilson-Henjum K, Caran KL, Minbiole KP, Seifert K (2011) Bicephalic amphiphile architecture affects antibacterial activity. Eur J Med Chem 46:4219–4226. https://doi.org/10.1016/j.ejmech

    Article  CAS  PubMed  Google Scholar 

  16. Lee YZ, Chen X, Chen SA, Wei PK, Fann WS (2001) Soluble electroluminescent poly(phenylene vinylene)s with balanced electron- and hole injections. J Am Chem Soc 123:2296–2307. https://doi.org/10.1021/ja003135d

    Article  CAS  PubMed  Google Scholar 

  17. Mueller R, Yang J, Duan C, Pop E, Zhang LH, Huang TB, Denisenko A, Denisko OV, Oniciu DC, Bisgaier CL, Pape ME, Freiman CD, Goetz B, Cramer CT, Hopson KL, Dasseux JL (2004) Long hydrocarbon chain ether diols and ether diacids that favorably alter lipid disorders in vivo. J Med Chem 47:5183–5197. https://doi.org/10.1021/jm0400395

    Article  CAS  PubMed  Google Scholar 

  18. Chakraborti AK, Chankeshwara SV (2009) Counterattack mode differential acetylative deprotection of phenylmethyl ethers: applications to solid phase organic reactions. J Org Chem 74:1367–1370. https://doi.org/10.1021/jo801659g

    Article  CAS  PubMed  Google Scholar 

  19. Yu DD, Lin W, Chen T, Forman BM (2013) Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery. Bioorg Med Chem 21:4266–4278. https://doi.org/10.1016/j.bmc.2013.04.069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goldwasser J, Cohen PY, Yang E, Balaguer P, Yarmush ML, Nahmias Y (2010) Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha. PLoS ONE 5:e12399. https://doi.org/10.1371/journal.pone.0012399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maestro, version 9.9 (2014) Schrödinger. LLC, New York, NY. www.schrodinger.com

Download references

Acknowledgements

The work was supported by National Natural Science Foundation of China (No. 81660571), Guangxi Natural Science Foundation of China (No. 2015GXNSFBA139124) and “Scientific and Technological Innovation Plan” (No. 16431903900) from Science and Technology Commission of Shanghai Municipality. The authors are very thankful to shanghai ChemPartner Co., Ltd and WuXi AppTec for experimental assistance.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy, Taizhou Hospital of Zhejiang Province, Xi Men Street No. 150, Linhai, 317000, Zhejiang Province, China

    Si-Yun Nian & Zheng-Li Jiang

  2. Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, 201203, China

    Si-Yun Nian, Guo-Ping Wang & Ying Xiao

  3. Aurisco Pharmaceutical (Yangzhou) Co., Ltd., Yangzhou, 225100, China

    Si-Yun Nian & Guo-Ping Wang

  4. College of Pharmacy, Guilin Medical University, Guilin, 541004, China

    Mo-Han Huang, Yi-Huan Zhou & Xiang-Duan Tan

Authors
  1. Si-Yun Nian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guo-Ping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zheng-Li Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mo-Han Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-Huan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiang-Duan Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiang-Duan Tan.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 685 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nian, SY., Wang, GP., Jiang, ZL. et al. Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists. Mol Divers 23, 19–33 (2019). https://doi.org/10.1007/s11030-018-9843-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-018-9843-2

Keywords

Search

Navigation