Structure‐activity profiles of macrolactam immunosuppressant FK‐506 analogues

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Abstract
The immunosuppressive agent FK‐506 has received much attention due to its efficacy and potency in the areas of transplant rejection and autoimmune disease. Calcineurin, a Ca2+‐calmodulin activated phosphatase, was recently implicated in the immunosuppressive mechanism of FK‐506. In our ongoing search for superior immunosuppressive agents, we have synthesized several analogues of FK‐506 and tested their mechanistic and immunosuppressive actions. It was found that C‐18 hydroxyl analogues of ascomycin, an analogue of FK‐506 also called FR900520, bound tightly to immunophilin FKBP‐12, but do not show any immunosuppressive activity in vitro or in vivo despite good bioavail‐ability. Further, they reverse the inhibition of calcineurin caused by FK‐506/FKBP‐12 complex.