title: Structure-activity profiles of macrolactam immunosuppressant FK-506 analogues.
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 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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: M
authors.initials: M
authors.lastname: Kawai
authors.forename: B C
authors.initials: BC
authors.lastname: Lane
authors.forename: G C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: K W
authors.initials: KW
authors.lastname: Mollison
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
authors.forename: J R
authors.initials: JR
authors.lastname: Luly
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D007376:Interleukin-2; C058028:immunomycin; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus