Inhibitors of the Apical Sodium-Dependent Bile Acid Transporter (ASBT) as Promising Drugs

Abstract

Inhibition of the apical sodium-dependent bile acid transporter (ASBT, also known as IBAT, the ileal bile acid transporter, SLC10A2) leads to impairments in the enterohepatic circulation of bile acids and their excretion with fecal masses. This is accompanied by cholesterol utilization for synthesis of new bile acids. ASBT inhibitors are promising drugs for the treatment of such diseases as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, type 2 diabetes mellitus, necrotic enterocolitis, chronic constipation, and atherosclerosis. To date the most known chemically synthesized inhibitors are: A3309, SHP626, A4250, 264W94, GSK2330672, SC-435. All of them are at different stages of clinical trials, which confirm high efficacy and good tolerance of these inhibitors. Current trends in this field also include directed chemical synthesis of ASBT inhibitors, as well as their search among substances of plant origin.

This is a preview of subscription content, access via your institution.

Fig. 1.
Fig. 2.
Fig. 3.

REFERENCES

  1. 1

    Chen, L., Yao, X., Young, A., McNulty, J., Anderson, D., Liu, Y., Nystrom, C., Croom, D., and Ross, S., Am. J. Physiol. Endocrinol. Metab., 2012, vol. 302, pp. 68–76. https://doi.org/10.1152/ajpendo.00323.2011

    CAS  Article  Google Scholar 

  2. 2

    Tiessen, R.G., Kennedy, C.A., Keller, B.T., Levin, N., Acevedo, L., Gedulin, B., Vliet, A.A., Dorenbaum, A., and Palmer, M., BMC Gastroenterology, 2018, vol. 18, no. 1, 3. https://doi.org/10.1186/s12876-017-0736-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Patti, M.E., Houten, S.M., and Bianco, A.C., Obesity, 2009, vol. 17, pp. 671–677. https://doi.org/10.1038/oby.2009.102

    CAS  Article  Google Scholar 

  4. 4

    Cyphert, H.A., Ge, X., Kohan, A.B., et al., J. Biol. Chem., 2012, vol. 287, no. 30, pp. 25123–25138. https://doi.org/10.1074/jbc.M112.375907

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Babaknejad, N., Nayeri, H., and Hemmati, R., Horm. Metab. Res., 2018, vol. 50, pp. 441–452. https://doi.org/10.1055/a-0623-2909

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Jia, W., Xie, G., and Jia, W., Gastroenterol. Hepatol., 2018, vol. 15, pp. 111–128. https://doi.org/10.1038/nrgastro.2017.119

    CAS  Article  Google Scholar 

  7. 7

    Chiang, J.Y. and Ferrell, J.M., Gene Expression, 2018, vol. 18, pp. 71–87. https://doi.org/10.3727/105221618X15156018385515

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ge, M., Niu, W., Ren, J., Cai, S., Yu, D., and Liu, H., Acta Pharmacologica Sinica, 2018, vol. 40, no. 7, pp. 895–907. https://doi.org/10.1038/s41401-018-0195-3

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Rao, A., Kosters, A., and Mells, J.E., Sci. Transl. Med., 2016, vol. 8, no. 357, 357ra122. https://doi.org/10.1126/scitranslmed.aaf4823

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Salic, K., Kleemann, R., Wilkins-Port, C., McNulty, J., Verschuren, L., and Palmer, M., PLoS One, 2019, vol. 14, no. 6, e0218459. https://doi.org/10.1371/journal.pone.0218459

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Siebers, N., Palmer, M., and Silberg, D.G., Eur. J. Drug Metab. Pharmacokinet., 2018, vol. 43, no. 1, pp. 91–101. https://doi.org/10.1007/s13318-017-0429-7

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Lundasen, T., Andersson, E.-M., Snaith, M., et al. PLoS One, 2012, vol. 7, no. 5, e37787. https://doi.org/10.1371/journal.pone.0037787

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Wu, Y., Aquino, C.J., and Cowan, D.J., J. Med. Chem., 2013, vol. 56, no. 12, pp. 5094–5114. https://doi.org/10.1021/jm400459m

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Halpern, M.D., Weitkamp, J.H., Patrick, S.K., Dobrenen, H.J., and Khailova, L.H., Am. J. Physiol. Gastrointest. Liver Physiol., 2010, vol. 299, pp. 623–631. https://doi.org/10.1152/ajpgi.00242.2010

    CAS  Article  Google Scholar 

  15. 15

    Chey, W.D., Camilleri, M., and Chang, L., Am. J. Gastroenterol., 2011, vol. 106, pp. 1803–1812. https://doi.org/10.1038/ajg.2011.162

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Nakajima, A., Seki, M., and Taniguchi, S., J. Gastroenterol., 2018, vol. 53, pp. 525–534. https://doi.org/10.1007/s00535-017-1383-5

    Article  PubMed  Google Scholar 

  17. 17

    Simren, M., Bajor, A., and Gillberg, P.-G., Aliment. Pharmacol. Ther., 2011, vol. 34, pp. 41–50. https://doi.org/10.1111/j.1365-2036.2011.04675.x

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Bhat, B.G., Rapp, S.R., and Beaudry, J.A., J. Lipid Res., 2003, vol. 44, pp. 1614–1621. https://doi.org/10.1194/jlr.M200469-JLR200

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Muthusamy, S., Malhotra, P., Hosameddin, M., Dudeja, A.K., Borthakur, S., Saksena, S., Gill, R.K., Dudeja, P.K., and Alrefai, W.A., Am. J. Physiol. Cell Physiol., 2015, vol. 308, no. 12, pp. 964–971. https://doi.org/10.1152/ajpcell.00023

    Article  Google Scholar 

  20. 20

    Saeki, T., Sato, K., Ito, S., Ikeda, K., and Kanamoto, R., BMC Physiol., 2013, vol. 13, 4. https://doi.org/10.1186/1472-6793-13-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Moore, R.H., Chothe, P., and Swaan, P.W., Biochemistry, 2013, vol. 52, no. 30, pp. 5117–5124. https://doi.org/10.1021/bi400028q

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Hussainzada, N., Da Silva, T.C., and Swaan, P.W., Biochemistry, 2009, vol. 48, no. 36, pp. 8528–8539. https://doi.org/10.1021/bi900616w

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Annaba, F., Sarwar, Z., Kumar, P., Saksena, S., Turner, J.R., Dudeja, P.K., Gill, R.K., and Alrefai, W.A., Am. J. Physiol. Gastrointest. Liver Physiol., 2008, vol. 294, no. 2, pp. 489–497. https://doi.org/10.1152/ajpgi.00237.2007

    CAS  Article  Google Scholar 

  24. 24

    da Silva, T.C., Hussainzada, N., Khantwal, C.M., Polli, J.E., and Swaan, P.W., J. Biol. Chem., 2011, vol. 286, no. 31, pp. 27322–27332. https://doi.org/10.1074/jbc.M110.217802

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Sabit, H., Mallajosyula, S.S., MacKerell, A.D., Jr., and Swaan, P.W., J. Biol. Chem., 2013, vol. 288, no. 45, pp. 32394–32404. https://doi.org/10.1074/jbc.M113.518555

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Hussainzada, N., Khandewal, A., and Swaan, P.W., Mol. Pharmacol., 2008, vol. 73, no. 2, pp. 305–313. https://doi.org/10.1124/mol.107.041640

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Paresh, P.C., Lindsay, C.C., Robyn, H.M., and Peter, W.S., Biochim. Biophys. Acta, 2017, vol. 1860, no. 3, pp. 645–653.  https://doi.org/10.1016/j.bbamem.2017.11.016

    CAS  Article  Google Scholar 

  28. 28

    Nakajima, A., Seki, M., and Taniguchi, S., Lancet Gastroenterol. Hepatol., 2018, vol. 3, no. 8, pp. 537–547. https://doi.org/10.1016/S2468-1253(18)30123-7

    Article  PubMed  Google Scholar 

  29. 29

    Wong, B.S., Camilleri, M., and McKinzie, S., Am. J. Gastroenterol., 2011, vol. 106, pp. 2154–2164. https://doi.org/10.1038/ajg.2011.285

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Pappachan, J.M., Babu, S., Krishnan, B., and Ravindran, N.C., J. Clin. Translat. Hepatol., 2017, vol. XX, pp. 1–10. https://doi.org/10.14218/JCTH.2017.00013

    Article  Google Scholar 

  31. 31

    Krivosheev, A.B., Kuimov, A.D., Bogoryanova, P.A., Popov, K.V., Kondratova, M.A., Gubanova, S.K., and Tuguleva, T.A., Siberian Medical Review, 2016, vol. 4, pp. 48–57.

    Article  Google Scholar 

  32. 32

    McCullough, A.J., J. Clin. Gastroenterol., 2006, vol. 40, no. 1, pp. S17–S29. https://doi.org/10.1097/01.mcg.0000168645.86658.22

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Morrison, M.C., Verschuren, L., and Salic, K., Hepatol. Commun., 2018, vol. 2, no. 12, pp. 1513–1532. https://doi.org/10.1002/hep4.1270

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Ikenaga, N., Liu, S.B., and Sverdlov, D.Y., Am. J. Pathol., 2015, vol. 185, no. 2, pp. 325–334. https://doi.org/10.1016/j.ajpath.2014.10.013

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Baghdasaryan, A., Fuchs, C.D., Österreicher, C.H., Lemberger, U.J., Halilbasic, E., Påhlman, I., Graffner, H., Krones, E., Fickert, P., Wahlström, A., Ståhlman, M., Paumgartner, G., Marschall, H.-U., and Trauner, M., J. Hepatol., 2016, vol. 64, pp. 674–681. https://doi.org/10.1016/j.jhep.2015.10.024

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Graffner, H., Gillberg, P.-G., Rikner, L., and Marschall, H.-U., Aliment. Pharmacol. Ther., 2016, vol. 43, pp. 303–310. https://doi.org/10.1111/apt.13457

    CAS  Article  PubMed  Google Scholar 

  37. 37

    de Azevedo, R.A., Takamatsu, F.Y., and Kondo, M., Rev. Soc. Bras. Clin. Med., 2017, vol. 15, no. 1, pp. 61–67.

    Google Scholar 

  38. 38

    Michalak, A., Hanc, M., and Fatyga, A., J. Pre-Clin. Clin. Res., 2011, vol. 5, no. 2, pp. 47–49.

    Google Scholar 

  39. 39

    Al-Dury, S., Wahlström, A., and Wahlin, S., Sci. Rep., 2018, vol. 8, 6658. https://doi.org/10.1038/s41598-018-25214-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Hegade, V.S., Kendrick, S.F.W., and Dobbins, R.L., Lancet, 2017, vol. 389, pp. 1114–1123. https://doi.org/10.1016/S0140-6736(17)30319-7

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Ino, H., Endo, A., and Wakamatsu, A., Clin. Pharmacol. Drug Develop., 2019, vol. 8, no. 1, pp. 70–77. https://doi.org/10.1002/cpdd.576

    CAS  Article  Google Scholar 

  42. 42

    West, K.L., Zern, T.L., Butteiger, D.N., Keller, B.T., and Fernandez, M.L., Atherosclerosis., 2003, vol. 171, pp. 201–210. https://doi.org/10.1016/j.atherosclerosis.2003.08.019

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Lo Sasso, G., Schlage, W.K., and Boué, S., J. Transl. Med., 2016, vol. 14, 146. https://doi.org/10.1186/s12967-016-0901-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Miethke, A.G., Zhang, W., and Simmons, J., Hepatology, 2016, vol. 63, no. 2, pp. 512–523. https://doi.org/10.1002/hep.27973

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Montagnesea, S., Russo, F.P., and Amodio, P., Digestive Liver Disease, 2019, vol. 51, pp. 190–205. https://doi.org/10.1016/j.dld.2018.11.035

    Article  Google Scholar 

  46. 46

    de Morrow, S., J. Clin. Exper. Hepatol., 2019, vol. 9, no. 1, pp. 117–124. https://doi.org/10.1016/j.jceh.2018.04.011

    Article  Google Scholar 

  47. 47

    Xie, G., Wang, X., and Jiang, R., EBioMedicine, 2018, vol. 37, pp. 294–306. https://doi.org/10.1016/j.ebiom.2018.10.030

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Liu, H.-T., He, H.-W., Bai, X.-G., Wang, J.-X., Xu, C.-L., Cai, S.-Y., Shao, R.-G., and Wang, Y.-C., Molecules, 2013, vol. 18, pp. 6883−6897. https://doi.org/10.3390/molecules18066883

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Liu, H., Pang, G., Ren, J., Zhao, Y., and Wang, J., Acta Pharmaceutica Sinica B., 2017, vol. 7, no. 2, pp. 223−229. https://doi.org/10.1016/j.apsb.2016.11.005

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Zheng, X., Ekins, S., Raufman, J.-P., and Polli, J.E., Molecular Pharmaceutics, 2009, vol. 6, no. 5, pp. 1591−1603. https://doi.org/10.1021/mp900163d

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Shi, A., Zhou, Y., and Zhang, X., Eur. J. Pharmaceut. Sci., 2017, vol. 102, pp. 220−229. https://doi.org/10.1016/j.ejps.2017.03.012

    CAS  Article  Google Scholar 

  52. 52

    Reygaert, W.C., Beverages, 2017, vol. 3, 6. https://doi.org/10.3390/beverages3010006

    CAS  Article  Google Scholar 

  53. 53

    Annaba, F., Kumar, P., and Dudeja, A.K., Am. J. Physiol. Gastrointest. Liver Physiol., 2010, vol. 298, pp. 467−473. https://doi.org/10.1152/ajpgi.00360.2009

    CAS  Article  Google Scholar 

  54. 54

    Kumar, D.S., Shankar, P., and Rao, G.U., Int. J. Pharmaceut. Sci. Nanotechnol., 2009, vol. 2, no. 1, pp. 407−412.

    Google Scholar 

  55. 55

    Chothe, P.P. and Swaan, P.W., J. Biochem., 2014, vol. 459, pp. 301−312. https://doi.org/10.1042/BJ20131428

    CAS  Article  Google Scholar 

  56. 56

    Zou, Z.-Y., Hu, Y.-R., Ma, H., Feng, M., Li, X.-G., and Ye, X.-L., Eur. J. Pharmacol., 2016, vol. 774, pp. 1−9. https://doi.org/10.1016/j.ejphar.2015.11.017

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Yi, J., Ye, X., Wang, D., He, K., Yang, Y., Liu, X., and Li, X., J. Ethnopharmacology, 2013, vol. 145, pp. 303−310. https://doi.org/10.1016/j.jep.2012.10.062

    CAS  Article  Google Scholar 

  58. 58

    Zarzour, R.H., Alshawsh, M.A., Asif, M., Al-Mansoub, M.A., Mohamed, Z., Ahmad, M., Majid, A.M., Asmawi, M.Z., Kaur, G., Al-Dualimi, D.W., and Yam, M.F., Nutrients, 2018, vol. 10, 1057. https://doi.org/10.3390/nu10081057

    CAS  Article  PubMed Central  Google Scholar 

  59. 59

    Poupon, R., J. Hepatology, 2016, vol. 64, pp. 537−538. https://doi.org/10.1016/j.jhep.2015.12.007

    CAS  Article  Google Scholar 

  60. 60

    Bajor, A., Gillberg, P.-G., and Abrahamsson, H., Scand. J. Gastroenterol., 2010, vol. 45, pp. 645−664. https://doi.org/10.3109/00365521003702734

    Article  PubMed  Google Scholar 

  61. 61

    Raufman, J.-P., Dawson, P.A., and Anuradha, R., Carcinogenesis, 2015, vol. 36, no. 10, pp. 1193−1200. https://doi.org/10.1093/carcin/bgv107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Gillberg, P.G., Dahlstrom, M., and Starke, I., Gastroenterology, 2010, vol. 138, no. 5, suppl. 1, 224. https://doi.org/10.1016/S0016-5085(10)61017-7

    Article  Google Scholar 

  63. 63

    Root, C., Smith, C.D., Sundseth, S.S., Pink, H.M., Wilson, J.G., and Lewis, M.C., J. Lipid Res., 2002, vol. 43, no. 8, pp. 1320−1323.

    CAS  Article  Google Scholar 

  64. 64

    Bhat, B.G., Rapp, S.R., Beaudry, J.A., Napawan, N., Butteiger, D.N., Hall, K.A., Null, C.L., Luo, Y., and Keller, B.T., J. Lipid Res., 2003, vol. 44, no. 9, pp. 1614−1621. https://doi.org/10.1194/jlr.M200469-JLR200

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Kramer, W., Stengelin, S., Baringhaus, K.H., Enhsen, A., Heuer, H., Becker. W., Corsiero, D., Girbig, F., Noll, R., and Weyland, C., J. Lipid Res., 1999, vol. 40, no. 9, pp. 1604−1617.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to E. E. Saveleva.

Ethics declarations

COMPLIANCE WITH ETHICAL STANDARDS

This article does not contain any research involving humans or the use of animals as objects.

CONFLICT OF INTEREST

The authors declare that they have no conflicts of inte-rest.

Additional information

Translated by A. Medvedev

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saveleva, E.E., Tyutrina, E.S., Nakanishi, T. et al. Inhibitors of the Apical Sodium-Dependent Bile Acid Transporter (ASBT) as Promising Drugs. Biochem. Moscow Suppl. Ser. B 15, 16–26 (2021). https://doi.org/10.1134/S1990750821010078

Download citation

Keywords:

  • ASBT
  • A3309
  • SHP626
  • А4250
  • 264W94
  • GSK2330672