title: A novel immunosuppressive 1alpha,25-dihydroxyvitamin D3 analog with reduced hypercalcemic activity.
abstract: 1Alpha,25-dihydroxyvitamin D3, the biologically active form of vitamin D3, is a potent immunomodulatory molecule; however, its clinical use as an immunosuppressant is limited due to its strong effects on calcium homeostasis and the risk of associated side-effects. Here, we present a representative of a novel class of vitamin D analogs that exhibits potent immunosuppressive activity in a murine model of contact hypersensitivity when applied systemically and is efficacious also at nonhypercalcemic dosages. In vitro analysis revealed a binding affinity of ZK 191784 to the vitamin D receptor comparable with 1,25-dihydroxyvitamin D3. This compound inhibits lymphocyte proliferation and secretion of tumor necrosis factor alpha and interleukin-12 in monocytes in a concentration-dependent manner, but with reduced potency and efficacy than 1,25-dihydroxy-vitamin D3. Treatment of human monocytes with this analog significantly reduces expression of major histocompatibility complex class II, B7.1, and intercellular adhesion molecule-1 equipotent to 1,25-dihydroxyvitamin D3. Interestingly, the compound failed to induce vitamin D-induced differentiation of human promyelocytic leukemia cell line HL-60 to monocytes and was capable of antagonizing the action of 1,25-dihydroxyvitamin D3. In vivo, as analyzed in mice the compound potently inhibits the contact hypersensitivity when applied systemically. ZK 191784 has a clear therapeutic advantage over 1,25-dihydroxyvitamin D3 by inducing immunosuppressive effects also at concentrations that do not cause hypercalcemia. ZK 191784 is the first representative of a novel class of vitamin D analogs that might have therapeutic potential in T cell-mediated immune disorders.
authors.affiliation: Research Business Area DermatologyMedicinal Chemistry and Center of Dermatology, Schering AG, 13342 Berlin, Germany. ulrich.zuegel@shering.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zügel
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Claudia
authors.initials: C
authors.lastname: Giesen
authors.forename: Khusru
authors.initials: K
authors.lastname: Asadullah
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D018122:B7-1 Antigen / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003877:Dermatitis, Contact / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced*; D007165:Immunosuppression Therapy / Q000379:methods*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D016207:Cytokines; D006684:HLA-DR Antigens; D008070:Lipopolysaccharides; D018167:Receptors, Calcitriol; C470666:ZK 191784; D018799:Intercellular Adhesion Molecule-1; D002117:Calcitriol