Structure-activity profiles of macrolactam immunosuppressant FK-506 analogues.
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 Ca(2+)-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 bioavailability. Further, they reverse the inhibition of calcineurin caused by FK-506/FKBP-12 complex.
Kawai
M
M
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064.
Lane
B C
BC
Hsieh
G C
GC
Mollison
K W
KW
Carter
G W
GW
Luly
J R
JR
D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D006965:Hyperplasia; D007376:Interleukin-2 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D007376:Interleukin-2; C058028:immunomycin; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus