The medicinal chemistry of FK-506


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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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).

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Key words

  • Macrolactams
  • FK-506
  • Ascomycin
  • Calcineurin