New vitamin D receptor agonists with decreased metabolic stability

Abstract

The aim of the study was the development of vitamin D receptor agonists with decreased metabolic stability for the topical treatment of psoriasis and related hyperproliferative skin diseases. Calcitriol analogues 1 , 2 , 3 , all of which contain modifications in the side chain, were synthesized. The obtained analogues were full agonists when the induction of CD14 expression in HL-60 cells, the induction of 5-lipoxygenase activity in Mono Mac 6 cells, and the inhibition of phytohemagglutinin (PHA)-stimulated lymphocyte proliferation were studied. The ec 50 value of the most active compound 1 was 1.2 nM in the CD14 assay and 1 nM in the 5-lipoxygenase assay, whereas calcitriol gave ec 50 values in these assays of 3.7 and 9 nM, respectively. In the lymphocyte proliferation assay, compound 1 and calcitriol had ic 50 values of 0.3 and 2.8 nM, respectively. All three compounds had receptor binding affinities similar to that of calcitriol. The compounds showed a decreased metabolic stability in rat liver homogenates and had a 50-fold lower affinity for the vitamin D-binding protein than calcitriol, which suggests that calcitriol analogues are metabolized more rapidly after systemic uptake or application. When injected into rats, the analogues displayed an approximately 100-fold lower hypercalcemic effect than calcitriol. In summary, our study presents three new and potent vitamin D receptor agonists with interesting profiles for development as antipsoriatic drugs.