Targeting bile acid receptors: Discovery of a potent and selective farnesoid X receptor agonist as a new lead in the pharmacological approach to liver diseases

Frontiers in Pharmacology

Volumn 8, Issue MAR, 2017, Pages

  Festa, Carmen ^a   De Marino, Simona ^a   Carino, Adriana ^b   Sepe, Valentina ^a   Marchianò, Silvia ^b   Cipriani, Sabrina ^b   Di Leva, Francesco S ^a   Limongelli, Vittorio ^a,c   Monti, Maria C ^d   Capolupo, Angela ^d   Distrutti, Eleonora ^e   Fiorucci, Stefano ^b   Zampella, Angela ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^b Dipartimento di Medicina Clinica e Sperimentale Nuova Facoltà di Medicina   (Italy)

^c UNIVERSITY OF LUGANO   (Switzerland)

^d UNIVERSITY OF SALERNO   (Italy)

^e SANTA MARIA DELLA MISERICORDIA HOSPITAL   (Italy)

Author keywords

Bile acid receptors; Bile acids; Cholestasis; Drug discovery; Farnesoid X receptor; Fibrosis; Liver disorders

Indexed keywords

3BETA AZIDO 6ALPHA ETHYL 7ALPHA HYDROXY 5BETA CHOLAN 24 OIC ACID; BILE ACID; BILE ACID RECEPTOR; FARNESOID X RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BSEP GENE; CONCENTRATION RESPONSE; CYP7A1 GENE; DRUG EFFICACY; DRUG MECHANISM; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; FGF21 GENE; GENE; GENE EXPRESSION; GENE TARGETING; HEP-G2 CELL LINE; HUMAN; HUMAN CELL; LIVER DISEASE; MALE; MOLECULAR DOCKING; MOUSE; NONHUMAN; OSTALPHA GENE; SHIP GENE; STRUCTURE ACTIVITY RELATION;

EID: 85018653499     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2017.00162     Document Type: Article

References (62)

1. Alemi, F., Kwon, E., Poole, D. P., Lieu, T., Lyo, V., Cattaruzza, F., et al. (2013). The TGR5 receptor mediates bile acid-induced itch and analgesia. J. Clin. Invest. 123, 1513-1530. doi: 10.1172/JCI64551
2. Anzini, M., Braile, C., Valenti, S., Cappelli, A., Vomero, S., Marinelli, L., et al. (2008). Ethyl 8-Fluoro-6-(3-nitrophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate as novel, highly potent, and safe antianxiety agent. J. Med. Chem. 51, 4730-4743. doi: 10.1021/jm8002944
3. Anzini, M., Valenti, S., Braile, C., Cappelli, A., Vomero, S., Alcaro, S., et al. (2011). New insight into the central benzodiazepine receptor-ligand interactions: design, synthesis, biological evaluation, and molecular modeling of 3-substituted 6-phenyl-4H-imidazo[1,5-a]-[1,4]benzodiazepines and related compounds. J. Med. Chem. 54, 5694-5711. doi: 10.1021/jm2001597
4. Cariou, B., van Harmelen, K., Duran-Sandoval, D., van Dijk, T. H., Grefhorst, A., Abdelkarim, M., et al. (2006). The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039-11049. doi: 10.1074/jbc.M510258200
5. Cerqueira, N. M., Gesto, D., Oliveira, E. F., Santos-Martins, D., Brás, N. F., Sousa, S. F., et al. (2015). Receptor-based virtual screening protocol for drug discovery. Arch. Biochem. Biophys. 582, 56-67. doi: 10.1016/j.abb.2015.05.011
6. Cipriani, S., Mencarelli, A., Palladino, G., and Fiorucci, S. (2010). FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid Res. 51, 771-784. doi: 10.1194/jlr.M001602
7. Copple, B. L., and Li, T. (2016). Pharmacology of bile acid receptors: evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol. Res. 104, 9-21. doi: 10.1016/j.phrs.2015.12.007
8. D'Amore, C., Di Leva, F. S., Sepe, V., Renga, B., Del Gaudio, C., D'Auria, M. V., et al. (2014). Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors. J. Med. Chem. 57, 937-954. doi: 10.1021/jm401873d
9. Di Leva, F. S., Festa, C., D'Amore, C., De Marino, S., Renga, B., D'Auria, M. V., et al. (2013). Binding mechanism of the farnesoid X receptor marine antagonist suvanine reveals a strategy to forestall drug modulation on nuclear receptors. Design, synthesis, and biological evaluation of novel ligands. J. Med. Chem. 56, 4701-4717. doi: 10.1021/jm400419e
10. Di Leva, F. S., Festa, C., Renga, B., Sepe, V., Novellino, E., Fiorucci, S., et al. (2015). Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism. Sci. Rep. 5:16605. doi: 10.1038/srep16605
11. Festa, C., Renga, B., D'Amore, C., Sepe, V., Finamore, C., De Marino, S., et al. (2014). 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. 57, 8477-8495. doi: 10.1021/jm501273r
12. Finamore, C., Festa, C., Renga, B., Sepe, V., Carino, A., Masullo, D., et al. (2016). Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands. Sci. Rep. 6:29320. doi: 10.1038/srep29320
13. Fiorucci, S. (2012). Current advances in therapeutic applications of nuclear receptors. Curr. Top. Med. Chem. 12, 484-485. doi: 10.2174/156802612799436696
14. Fiorucci, S., Antonelli, E., Rizzo, G., Renga, B., Mencarelli, A., Riccardi, L., et al. (2004). The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127, 1497-1512. doi: 10.1053/j.gastro.2004.08.001
15. Fiorucci, S., and Baldelli, F. (2009). Farnesoid X receptor agonists in biliary tract disease. Curr. Opin. Gastroenterol. 25, 252-259. doi: 10.1097/MOG.0b013e328324f87e
16. Fiorucci, S., Cipriani, S., Baldelli, F., and Mencarelli, A. (2010a). Bile acid-activated receptors in the treatment of dyslipidemia and related disorders. Prog. Lipid Res. 49, 171-185. doi: 10.1016/j.plipres.2009.11.001
17. Fiorucci, S., Cipriani, S., Mencarelli, A., Baldelli, F., Bifulco, G., and Zampella, A. (2011a). Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA. Mini Rev. Med. Chem. 11, 753-762. doi: 10.2174/138955711796355258
18. Fiorucci, S., Cipriani, S., Mencarelli, A., Renga, B., Distrutti, E., and Baldelli, F. (2010b). Counter-regulatory role of receptors in immunity and inflammation. Curr. Mol. Med. 10, 579-595. doi: 10.2174/1566524011009060579
19. Fiorucci, S., and Distrutti, E. (2015). Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol. Med. 21, 702-714. doi: 10.1016/j.molmed.2015.09.001
20. Fiorucci, S., Distrutti, E., Ricci, P., Giuliano, V., Donini, A., and Baldelli, F. (2014). Targeting FXR in cholestasis: hyde or hope. Expert Opin. Ther. Targets 12, 1449-1459. doi: 10.1517/14728222.2014.956087
21. Fiorucci, S., Mencarelli, A., Cipriani, S., Renga, B., Palladino, G., Santucci, L., et al. (2011b). Activation of the farnesoid-X receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice. Br. J. Pharmacol. 164, 1929-1938. doi: 10.1111/j.1476-5381.2011.01481.x
22. Fiorucci, S., Mencarelli, A., Distrutti, E., Palladino, G., and Cipriani, S. (2010c). Targeting farnesoid-X-receptor: from medicinal chemistry to disease treatment. Curr. Med. Chem. 17, 139-159. doi: 10.2174/092986710790112666
23. Fiorucci, S., Mencarelli, A., Distrutti, E., and Zampella, A. (2012a). Farnesoid X receptor: from medicinal chemistry to clinical applications. Future Med. Chem. 4, 877-891. doi: 10.4155/fmc.12.41
24. Fiorucci, S., Mencarelli, A., Palladino, G., and Cipriani, S. (2009). Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol. Sci. 30, 570-580. doi: 10.1016/j.tips.2009.08.001
25. Fiorucci, S., Rizzo, G., Donini, A., Distrutti, E., and Santucci, L. (2007). Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol. Med. 13, 298-309. doi: 10.1016/j.molmed.2007.06.001
26. Fiorucci, S., Zampella, A., and Distrutti, E. (2012b). Development of FXR, PXR and CAR agonists and antagonists for treatment of liver disorders. Curr. Top. Med. Chem. 12, 605-624. doi: 10.2174/156802612799436678
27. Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., et al. (2004). Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47, 1739-1749. doi: 10.1021/jm0306430
28. Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., et al. (2000). A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell. 6, 517-526. doi: 10.1016/S1097-2765(00)00051-4
29. Greenwood, J. R., Calkins, D., Sullivan, A. P., and Shelley, J. C. (2010). Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J. Comput. Aided Mol. Des. 24, 591-604. doi: 10.1007/s10822-010-9349-1
30. Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., et al. (2004). Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47, 1750-1759. doi: 10.1021/jm030644s
31. Heckmann, D., Laufer, B., Marinelli, L., Limongelli, V., Novellino, E., Zahn, G., et al. (2009). Breaking the dogma of the metal-coordinating carboxylate group in integrin ligands: introducing hydroxamic acids to the MIDAS to tune potency and selectivity. Angew. Chem. Int. Ed. Engl. 48, 4436-4440. doi: 10.1002/anie.200900206
32. Harder, E., Damm, W., Maple, J., Wu, C., Reboul, M., Xiang, J. Y., et al. (2016). OPLS3: A force field providing broad coverage of drug-like small molecules and proteins. J. Chem. Theory Comput. 12, 281-296. doi: 10.1021/acs.jctc.5b00864
33. Hodge, R. J., and Nunez, D. J. (2016). Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype? Diabetes Obes. Metab. 18, 439-443. doi: 10.1111/dom.12636
34. John, C., Werner, P., Worthmann, A., Wegner, K., Tödter, K., Scheja, L., et al. (2014). A liquid chromatography-tandem mass spectrometry-based method for the simultaneous determination of hydroxy sterols and bile acids. J. Chromatogr. A 1371, 184-195. doi: 10.1016/j.chroma.2014.10.064
35. Kawamata, Y., Fujii, R., Hosoya, M., Harada, M., Yoshida, H., Miwa, M., et al. (2003). A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435-9440. doi: 10.1074/jbc.M209706200
36. Kliewer, S. A., and Mangelsdorf, D. J. (2015). Bile acids as hormones: the FXR-FGF15/19 Pathway. Dig. Dis. 33, 327-331. doi: 10.1159/000371670
37. Li, T., Holmstrom, S. R., Kir, S., Umetani, M., Schmidt, D. R., Kliewer, S. A., et al. (2011). The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol. Endocrinol. 25, 1066-1071. doi: 10.1210/me.2010-0460
38. Lieu, T., Jayaweera, G., Zhao, P., Poole, D. P., Jensen, D., Grace, M., et al. (2014). The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 147, 1417-1428. doi: 10.1053/j.gastro.2014.08.042
39. Lin, W., Zhang, X., He, Z., Jin, Y., Gong, L., and Mi, A. (2002). Reduction of azides to amines or amides with zinc and ammonium chloride as reducing agent. Synth. Commun. 32, 3279-3284. doi: 10.1081/SCC-120014032
40. Makishima, M., Okamoto, A. Y., Repa, J. J., Tu, H., Learned, R. M., Luk, A., et al. (1999). Identification of a nuclear receptor for bile acids. Science 284, 1362-1365. doi: 10.1126/science.284.5418.1362
41. Maruyama, T., Miyamoto, Y., Nakamura, T., Tamai, Y., Okada, H., Sugiyama, E., et al. (2002). Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714-719. doi: 10.1016/S0006-291X(02)02550-0
42. Mason, A., Luketic, V., Lindor, K., Hirschfield, G., Gordon, S., Mayo, M., et al. (2010). Farnesoid-X receptor agonists: a new class of drugs for the treatment of PBCγ An international study evaluating the addition of INT-747 to ursodeoxycholic acid. J. Hepatol. 52, S1-S2. doi: 10.1016/S0168-8278(10)60004-9
43. Mencarelli, A., Renga, B., D'Amore, C., Santorelli, C., Graziosi, L., Bruno, A., et al. (2013). Dissociation of intestinal and hepatic activities of FXR and LXRa supports metabolic effects of terminal ileum interposition in rodents. Diabetes Metab. Res. Rev. 62, 3384-3393. doi: 10.2337/db13-0299
44. Mi, L. Z., Devarakonda, S., Harp, J. M., Han, Q., Pellicciari, R., Willson, T. M., et al. (2003). Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol. Cell 11, 1093-1100. doi: 10.1016/S1097-2765(03)00112-6
45. Neuschwander-Tetri, B. A., Loomba, R., Sanyal, A. J., Lavine, J. E., Van Natta, M. L., Abdelmalek, M. F., et al. (2015). Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956-965. doi: 10.1016/S0140-6736(14)61933-4
46. Parks, D. J., Blanchard, S. G., Bledsoe, R. K., Chandra, G., Consler, T. G., Kliewer, S. A., et al. (1999). Bile acids: natural ligands for an orphan nuclear receptor. Science 284, 1365-1368. doi: 10.1126/science.284.5418.1365
47. Pellicciari, R., Fiorucci, S., Camaioni, E., Clerici, C., Costantino, G., Maloney, P. R., et al. (2002). 6-alpha-etyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45, 3569-3572. doi: 10.1021/jm025529g
48. Pellicciari, R., Passeri, D., De Franco, F., Mostarda, S., Filipponi, P., Colliva, C., et al. (2016). Discovery of 3a,7a,11β-trihydroxy-6a-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. 59, 9201-9214. doi: 10.1021/acs.jmedchem.6b01126
49. Schrödinger (2016a). Glide, Version 7.1. New York, NY: Schrödinger, LLC.
50. Schrödinger (2016b). LigPrep. New York, NY: Schrödinger, LLC.
51. Schrödinger (2016c). Maestro. New York, NY: Schrödinger, LLC.
52. Schrödinger (2016d). MacroModel. New York, NY: Schrödinger, LLC.
53. Sepe, V., Distrutti, E., Fiorucci, S., and Zampella, A. (2015a). Farnesoid X receptor modulators (2011-2014): a patent review. Expert Opin. Ther. Pat. 25, 885-896. doi: 10.1517/13543776.2015.1045413
54. Sepe, V., Distrutti, E., Limongelli, V., Fiorucci, S., and Zampella, A. (2015b). Steroidal scaffolds as FXR and GPBAR1 ligands: from chemistry to therapeutical application. Future Med. Chem. 7, 1109-1135. doi: 10.4155/fmc.15.54
55. Sepe, V., Festa, C., Renga, B., Carino, A., Cipriani, S., Finamore, C., et al. (2016). Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists. Sci. Rep. 6:19008. doi: 10.1038/srep19008
56. Shelley, J. C., Cholleti, A., Frye, L. L., Greenwood, J. R., Timlin, M. R., and Uchimaya, M. (2007). Epik: a software program for pKa prediction and protonation state generation for drug-like molecules. J. Comput. Aided Mol. Des. 21, 681-691. doi: 10.1007/s10822-007-9133-z
57. Swanson, H. I., Wada, T., Xie, W., Renga, B., Zampella, A., Distrutti, E., et al. (2013). Role of nuclear receptors in lipid dysfunction and obesity-related diseases. Drug Metab. Dispos. 41, 1-11. doi: 10.1124/dmd.112.048694
58. vanNierop, F. S., Scheltema, M. J., Eggink, H. M., Pols, T. W., Sonne, D. P., Knop, F. K., et al. (2017). Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol. 5, 224-233. doi: 10.1016/S2213-8587(16)30155-3
59. Vassileva, G., Golovko, A., Markowitz, L., Abbondanzo, S. J., Zeng, M., Yang, S., et al. (2006). Targeted deletion of GPBAR1 protects mice from cholesterol gallstone formation. Biochem. J. 398, 423-430. doi: 10.1042/BJ20060537
60. Wang, H., Chen, J., Hollister, K., Sowers, L. C., and Forman, B. M. (1999). Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3, 543-553. doi: 10.1016/S1097-2765(00)80348-2
61. Wang, L., Lee, Y. K., Bundman, D., Han, Y., Thevananther, S., Kim, C. S., et al. (2002). Redundant pathways for negative feedback regulation of bile acid production. Dev. Cell. 2, 721-731. doi: 10.1016/S1534-5807(02)00187-9
62. Zhang, Y., Lee, F. Y., Barrera, G., Lee, H., Vales, C., Gonzalez, F. J., et al. (2006). Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl. Acad. Sci. U.S.A. 103, 1006-1011. doi: 10.1073/pnas.0506982103