1. Research Business Area Dermatology, Schering AG, 13342 Berlin, Germany
2. ^*Medicinal Chemistry Schering AG, 13342 Berlin, Germany
3. ^†Center of Dermatology, Schering AG, 13342 Berlin, Germany

Correspondence: Dr Ulrich Zügel, Research Business Area Dermatology, Schering Research Laboratories, Müllerstrasse 178, 13342 Berlin, Germany. Email: ulrich.zuegel@schering.de

Received 29 April 2002; Revised 12 August 2002; Accepted 11 September 2002.

Abstract

1,25-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 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.