Glucocorticoid (GC) signalling is essential for normal fetal lung development. During late gestation a surge of endogenous GCs rapidly matures the lung by thinning the mesenchymal tissue and driving an increase in alveolar gas exchange surface area. Currently in situations of imminent preterm birth potent synthetic GCs such as betamethasone or dexamethasone (Dex) are administered antenatally to accelerate fetal lung maturation and reduce the risk of respiratory distress syndrome. There are however growing concerns that systemic exposure to powerful synthetic GCs is associated with detrimental side effects, particularly in the developing fetal brain. We are currently assessing novel activatable and selective partial agonists of the glucocorticoid receptor (GR) as new potential antenatal steroid treatments of preterm birth. One such GR agonist is a steroid prodrug called ciclesonide (Cic) that is activated in vivo by a family of intracellular serine-esterase enzymes, called the carboxylesterases (Ces), that are predominantly expressed in peripheral organs but are virtually absent in the brain. We have compared the effect of inactive and activated ciclesonide to dexamethasone for the regulation of key GR-regulated respiratory genes. Ciclesonide activity in the fetal lung was assessed by culturing primary mouse fetal fibroblast cells from wild-type and GR-null mice and treating them with Dex, Cic and its active compound, Des-Cic, for six hours. Changes in the fibroblast transcriptome was assessed by microarray analysis and RT-qPCR. Analysis of the top 30 induced and repressed genes illustrate that Dex and Des-Cic have similar activity profiles. Additionally, analysis of induced mRNA levels for four known GR induced genes, Fkbp5, Crispld2, Tgm2 and Zbtb16, showed that the active GR agonist Des-Cic strongly induced expression of these genes, and utilises functional GR to exert their effects. The data suggests that Cic regulates important respiratory genes in a similar fashion to Dex.