The medicinal chemistry of FK-506

Summary

Substantial strides have been made in the past decade in the discovery of potent immunosuppressants that are effective in the prevention of rejection in organ transplantation and in the treatment of autoimmune diseases. The past three years have witnessed stunning breakthroughs in the elucidation of the common mechanism of immunosuppressive action of FK-506 and cyclosporin A (CsA). FK-506 is 50- to 100-fold more potent than CsA in its immunosuppressive activity in vitro and in vivo, but retains the toxic side effects of CsA. This review describes the medicinal chemical evaluation of FK-506 with the objective of identifying positions on the macrolactam that can be altered without substantially reducing immunosuppressive activity. Suitable modification at such positions may reduce toxicity, thereby improving the overall therapeutic index and broadening the patient population that can be treated for autoimmune-related diseases.

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References

  1. 1

    Borel, J.F., Fuerer, C., Gubler, H.U. and Stahelen, H., Agents Actions, 6 (1976) 468.

    Google Scholar 

  2. 2

    Parsons, W.H., Sigal, N.H. and Wyvratt, M.J., Ann. New York Acad. Sci., 685 (1993) 22.

    Google Scholar 

  3. 3

    Kino, T., Hatanaka, H., Hashimoto, M., Nishiyama, M., Goto, T., Okuhara, M., Kohsaka, M., Aoki, H. and Imanaka, H., J. Antibiot., 40 (1987) 1249.

    Google Scholar 

  4. 4

    Sequeira, L.A., Hammond, P. and Cutler, R.E., Dialysis Transplant., (1992) 810.

  5. 5

    Textor, S.C., Wiesner, R., Wilson, D.J., Porayko, M., Romero, J.C., Burnett Jr., J.C., Gores, G., Hay, E., Dickson, E.R. and Krom, R.A., Transplantation, 55 (1993) 1332.

    Google Scholar 

  6. 6

    McDiarmid, S.V., Colonna II, J.O., Shakad, A., Ament, M.E. and Busuttil, R.W., Transplantation, 56 (1993) 847.

    Google Scholar 

  7. 7

    Vincent, S.H., Karanam, B.V., Painter, S.K. and Chiu, S.-H.L., Arch. Biochem. Biophys., 294 (1992) 454.

    Google Scholar 

  8. 8

    Besarab, A., Jarrell, B.E., Hirsch, S., Carabasi, R.A., Cressman, M.D. and Green, P., Transplantation, 44 (1987) 195.

    Google Scholar 

  9. 9

    Goulet, M.T., Mills, S.G., Parsons, W.H., Rupprecht, K.M. and Wyvratt, M.J., In Lukas, G. (Ed.) Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products, Vol. 2, Springer Verlag, 1993, pp. 141–212.

  10. 10

    Dumont, F.J., Staruch, M.J., Koprak, S.L., Melino, M.R. and Sigal, N.H., J. Immunol., 144 (1990) 251.

    Google Scholar 

  11. 11

    Tocci, M.J., Matkovich, D.A., Collier, K.A., Kwok, P., Dumont, F.J., Lin, C.S., Degudicibus, S., Siekierka, J.J., Chin, J. and Hutchinson, N.I., J. Immunol., 143 (1989) 718.

    Google Scholar 

  12. 12

    Dumont, F.J., Staruch, M.J., Koprack, S.L., Fischer, P.A. and Sigal, N.A., J. Immunol., 144 (1990) 1418.

    Google Scholar 

  13. 13

    Liu, J., Farmer, J.D., Lane, W.S., Friedman, J., Weissman, I. and Schreiber, S.L., Cell, 66 (1991) 807.

    Google Scholar 

  14. 14

    Chung, J., Kuo, C.J., Crabtree, G.R. and Blenis, J., Cell, 69 (1992) 1227.

    Google Scholar 

  15. 15

    Dumont, F.J., Staruch, M.J., Koprak, S.L., Siekierka, J.J., Lin, S.L., Harrison, R., Sewell, T., Kindt, V.M., Beattie, T.R., Wyvratt, M.J. and Sigal, N.H., J. Exp. Med., 176 (1992) 751.

    Google Scholar 

  16. 16

    Harrison, R.K. and Stein, R.L., Biochemistry, 29 (1990) 3813.

    Google Scholar 

  17. 17

    Arai, T.Y., Koyama, T., Suenaga, T. and Honda, H., J. Antibiot., 15 (1962) 231.

    Google Scholar 

  18. 18

    Borris, R.P., Byrne, K.M., Arison, B.H., Zink, D.L., Vesey, D.M., Dumont, F., Garrity, G.M., Monaghan, R.L., Kaplan, L. and Albers-Schonberg, G., unpublished results.

  19. 19

    Byrne, K.M., Shafiee, A., Nielsen, J.B., Arison, B., Monaghan, R.L. and Kaplan, L., In Nash, C. (Ed.) Microbial Metabolites, Developments in Industrial Microbiology Series, Wm. C. Brown, Dubuque 32 (1992) 29.

    Google Scholar 

  20. 20

    Ruby, C.L., Danis, S.J. and Arison, B.H., EPO Patent Publication 0,388,152, 1992.

  21. 21

    Byrne, K., Arison, B., Borris, R.P., Dumont, F., Vesey, D.M., Nallin, M.K., Monaghan, R.L. and Kaplan, L., unpublished results.

  22. 22

    VanDyne, G.D., Standaert, R.F., Karplus, P.A., Schreiber, S.L. and Clardy, J., Science, 252 (1991) 839.

    Google Scholar 

  23. 23

    Becker, J.W., Rotonda, J., McKeever, B.M., Chan, K., Marcy, A.I., Wiederrecht, G., Hermes, J.D. and Springer, J.P., J. Biol. Chem., 268 (1993) 11335.

    Google Scholar 

  24. 24

    Askin, D., Reamer, R.A., Joe, D., Volante, R.P. and Shinkai, I., J. Org. Chem., 55 (1990) 5448.

    Google Scholar 

  25. 25

    Hatanaka, H., Kino, T., Asano, M., Goto, T., Tanaka, H. and Okuhara, M., J. Antibiot., 42 (1989) 620.

    Google Scholar 

  26. 26

    Askin, D., Reamer, R.A., Jones, T.K., Volante, R.P. and Shinkai, I., Tetrahedron Lett., 30 (1989) 671.

    Google Scholar 

  27. 27

    Emmer, G. and Webber-Roth, S., Tetrahedron, 48 (1992) 5861.

    Google Scholar 

  28. 28

    Rupprecht, K.R. and Baker, R.K., unpublished results.

  29. 29

    Donald, D.K., Cooper, M.E., Furber, M., Wells, E., Hutchinson, R. and Black, F.M., Tetrahedron Lett., 32 (1991) 1375.

    Google Scholar 

  30. 30

    Goulet, M.T., Beattie, T.R. and Wyvratt, M.J., U.S. Patent 5,189,042, 1993.

  31. 31

    Donald, D.K., Furber, M., Hardern, D.N. and Leff, P., PCT Patent Publication WO 91/04025, 1991.

  32. 32

    Kasahara, C., Ohkawa, T. and Hashimoto, M., PCT Patent Publication WO 92/00313, 1992.

  33. 33

    Organ, H.M., Holmes, M.A., Pisano, J.M., Staruch, M.J., Wyvratt, M.J., Dumont, F.J. and Sinclair, P.J., Biomed. Chem. Lett., 3 (1993) 657.

    Google Scholar 

  34. 34

    Donald, D.K. and Furber, M., PCT Patent Publication WO 92/03441, 1992.

  35. 35

    Goulet, M.T. and Hodkey, D.W., EPO Patent Publication 0,455,427, 1991.

  36. 36

    Cooper, M.E., Donald, D.K. and Haredern, D.N., EPO Patent Publication 323,042, 1989.

  37. 37

    Rupprecht, K.R. and Ok, H., unpublished results.

  38. 38

    Sinclair, P.J., unpublished results.

  39. 39

    Bochis, R.J., unpublished results.

  40. 40

    Donald, D.K., Hardern, D.N., Cooper, M.E., Furber, M., Hashimoto, M., Kasahara, C. and Ohkawa, T., PCT Patent Publication WO 91/02736, 1991.

  41. 41

    Kasahara, C., Ohkawa, T. and Hashimoto, M., PCT Patent Publication WO 91/13899, 1991.

  42. 42

    Barton, D.H.R. and Finet, J.-P., Pure Appl. Chem., 59 (1987) 937.

    Google Scholar 

  43. 43

    Finet, J.-P., Chem. Rev., 89 (1989) 1487.

    Google Scholar 

  44. 44

    Sinclair, P.J., Wong, F., Wyvratt, M.W., Staruch, M.J. and Dumont, F., private communication.

  45. 45

    Goulet, M.T., Hodkey, D.W., Staruch, M.J., Dumont, F.J., Lin, S., Hung, S.H.Y., Siekierka, J.J. and Wyvratt, M.J., Biomed. Chem. Lett., 4 (1994) 927.

    Google Scholar 

  46. 46

    Goulet, M.T., Hodkey, D.W., Staruch, M.J., Dumont, F.J., Cryan, J.G., Parsons, W.H. and Wyvratt, M.J., Biomed. Chem. Lett., 4 (1994) 921.

    Google Scholar 

  47. 47

    Fujita, T., Iwasa, J. and Hansch, C., J. Am. Chem. Soc., 86 (1964) 5175. π is defined as: π=log Px − log PH, where PH is the octanol-water partition coefficient of the parent compound and PX is the partition coefficient of the derivative associated with the aromatic substitutent.

    Google Scholar 

  48. 48

    Goulet, M.T. and Wyvratt, M.J., U.S. Patent 5,162,334, 1992.

  49. 49

    Beattie, T.R., Fisher, M.J., Goulet, M.T., Ok, H.O. and Wyvratt, M.J., U.S. Patent 5,208,228, 1993.

    Google Scholar 

  50. 50

    Ok, H.O., Goulet, J. and Sinclair, P.J., U.S. Patent 5,208,241, 1993.

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Correspondence to William H. Parsons.

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Goulet, M.T., Rupprecht, K.M., Sinclair, P.J. et al. The medicinal chemistry of FK-506. Perspectives in Drug Discovery and Design 2, 145–162 (1994). https://doi.org/10.1007/BF02171741

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Key words

  • Macrolactams
  • FK-506
  • Ascomycin
  • Calcineurin