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Discovery of novel and orally active FXR agonists for the potential treatment of dyslipidemia & diabetes.

Richter HG, Benson GM, Blum D, Chaput E, Feng S, Gardes C, Grether U, Hartman P, Kuhn B, Martin RE, Plancher JM, Rudolph MG, Schuler F, Taylor S, Bleicher KH
Bioorg Med Chem Lett 21 191-4 (2011)
Cited: 33 times
EuropePMC logo PMID: 21134747

Abstract

Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.

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  2. Side-Chain Conformational Preferences Govern Protein-Protein Interactions. Watkins AM, Bonneau R, Arora PS. J Am Chem Soc 138 10386-10389 (2016)
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  4. Modern drug design: the implication of using artificial neuronal networks and multiple molecular dynamic simulations. Yakovenko O, Jones SJM. J Comput Aided Mol Des 32 299-311 (2018)


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  1. Chemistry and biology of multicomponent reactions. Dömling A, Wang W, Wang K. Chem Rev 112 3083-3135 (2012)
  2. The therapeutic journey of benzimidazoles: a review. Bansal Y, Silakari O. Bioorg Med Chem 20 6208-6236 (2012)
  3. Bile-ology: from bench to bedside. Jin LH, Fang ZP, Fan MJ, Huang WD. J Zhejiang Univ Sci B 20 414-427 (2019)
  4. Farnesoid X receptor modulators (2011 - 2014): a patent review. Sepe V, Distrutti E, Fiorucci S, Zampella A. Expert Opin Ther Pat 25 885-896 (2015)
  5. Characterizing ligands for farnesoid X receptor--available in vitro test systems for farnesoid X receptor modulator development. Merk D, Steinhilber D, Schubert-Zsilavecz M. Expert Opin Drug Discov 9 27-37 (2014)

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  2. Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids. Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR. Am J Physiol Gastrointest Liver Physiol 304 G940-8 (2013)
  3. Asymmetric phosphoric acid-catalyzed four-component Ugi reaction. Zhang J, Yu P, Li SY, Sun H, Xiang SH, Wang JJ, Houk KN, Tan B. Science 361 eaas8707 (2018)
  4. Pharmacophore-based discovery of FXR-agonists. Part II: identification of bioactive triterpenes from Ganoderma lucidum. Grienke U, Mihály-Bison J, Schuster D, Afonyushkin T, Binder M, Guan SH, Cheng CR, Wolber G, Stuppner H, Guo DA, Bochkov VN, Rollinger JM. Bioorg Med Chem 19 6779-6791 (2011)
  5. Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Hsu CW, Zhao J, Huang R, Hsieh JH, Hamm J, Chang X, Houck K, Xia M. Sci Rep 4 6437 (2014)
  6. Pharmacophore-based discovery of FXR agonists. Part I: Model development and experimental validation. Schuster D, Markt P, Grienke U, Mihaly-Bison J, Binder M, Noha SM, Rollinger JM, Stuppner H, Bochkov VN, Wolber G. Bioorg Med Chem 19 7168-7180 (2011)
  7. Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr -/- mice versus hamsters. Gardès C, Chaput E, Staempfli A, Blum D, Richter H, Benson GM. J Lipid Res 54 1283-1299 (2013)
  8. NSAIDs Ibuprofen, Indometacin, and Diclofenac do not interact with Farnesoid X Receptor. Schmidt J, Klingler FM, Proschak E, Steinhilber D, Schubert-Zsilavecz M, Merk D. Sci Rep 5 14782 (2015)
  9. Combining self- and cross-docking as benchmark tools: the performance of DockBench in the D3R Grand Challenge 2. Salmaso V, Sturlese M, Cuzzolin A, Moro S. J Comput Aided Mol Des 32 251-264 (2018)
  10. Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone. Yang L, Broderick D, Jiang Y, Hsu V, Maier CS. Biochim Biophys Acta 1844 1684-1693 (2014)
  11. Binding free energy predictions of farnesoid X receptor (FXR) agonists using a linear interaction energy (LIE) approach with reliability estimation: application to the D3R Grand Challenge 2. Rifai EA, van Dijk M, Vermeulen NPE, Geerke DP. J Comput Aided Mol Des 32 239-249 (2018)
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  13. Using physics-based pose predictions and free energy perturbation calculations to predict binding poses and relative binding affinities for FXR ligands in the D3R Grand Challenge 2. Athanasiou C, Vasilakaki S, Dellis D, Cournia Z. J Comput Aided Mol Des 32 21-44 (2018)
  14. Asymmetric synthesis of the four diastereoisomers of a novel non-steroidal farnesoid X receptor (FXR) agonist: role of the chirality on the biological activity. Marinozzi M, Carotti A, Sardella R, Buonerba F, Ianni F, Natalini B, Passeri D, Rizzo G, Pellicciari R. Bioorg Med Chem 21 3780-3789 (2013)
  15. Simultaneous diastereo- and enantioseparation of farnesoid X receptor (FXR) agonists with a quinine carbamate-based chiral stationary phase. Sardella R, Marinozzi M, Ianni F, Lisanti A, Natalini B. Anal Bioanal Chem 405 847-862 (2013)
  16. A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice. Heitel P, Faudone G, Helmstädter M, Schmidt J, Kaiser A, Tjaden A, Schröder M, Müller S, Schierle S, Pollinger J, Merk D. Commun Chem 3 174 (2020)
  17. Blinded evaluation of farnesoid X receptor (FXR) ligands binding using molecular docking and free energy calculations. Selwa E, Elisée E, Zavala A, Iorga BI. J Comput Aided Mol Des 32 273-286 (2018)
  18. CDOCKER and λ-dynamics for prospective prediction in D₃R Grand Challenge 2. Ding X, Hayes RL, Vilseck JZ, Charles MK, Brooks CL. J Comput Aided Mol Des 32 89-102 (2018)
  19. Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines. Ben Abdessalem A, Abderrahim R, Agrebie A, Dos Santos A, El Kaïm L, Khomenko A. Chem Commun (Camb) 51 1116-1119 (2015)
  20. Workflows and performances in the ranking prediction of 2016 D3R Grand Challenge 2: lessons learned from a collaborative effort. Gao YD, Hu Y, Crespo A, Wang D, Armacost KA, Fells JI, Fradera X, Wang H, Wang H, Sherborne B, Verras A, Peng Z. J Comput Aided Mol Des 32 129-142 (2018)
  21. Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists. Dehmlow H, Alvarez Sánchez R, Bachmann S, Bissantz C, Bliss F, Conde-Knape K, Graf M, Martin RE, Obst Sander U, Raab S, Richter HG, Sewing S, Sprecher U, Ullmer C, Mattei P. Bioorg Med Chem Lett 23 4627-4632 (2013)
  22. Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy. Concepción O, Belmar J, F de la Torre A, M Muñiz F, Pertino MW, Alarcón B, Ormazabal V, Nova-Lamperti E, Zúñiga FA, Jiménez CA. Molecules 25 E1911 (2020)
  23. eTOX ALLIES: an automated pipeLine for linear interaction energy-based simulations. Capoferri L, van Dijk M, Rustenburg AS, Wassenaar TA, Kooi DP, Rifai EA, Vermeulen NPE, Geerke DP. J Cheminform 9 58 (2017)
  24. Pharmacophore modeling, 3D-QSAR and molecular docking studies of benzimidazole derivatives as potential FXR agonists. Sindhu T, Srinivasan P. J Recept Signal Transduct Res 34 241-253 (2014)


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