Novel VDR antagonists based on the GW0742 scaffold.

The vitamin D receptor is a nuclear hormone receptor that regulates cell proliferation, cell differentiation and calcium homeostasis. The receptor is endogenously activated by 1,25-dihydroxyvitamin D3 , which induces transcription of VDR targets genes regulated by coactivator binding. VDR antagonists and partial agonists have been developed based on the secosteroid scaffold of vitamin D. Only a few non-secosteroid VDR antagonists are known. Herein, we report the rational design of non-secosteroid VDR antagonists using GW0742 as a scaffold. GW0742 is a PPARδ agonist previously identified by our group as a VDR antagonist. Several modifications including the replacement of the thiazole ring with an oxazole ring led to compound 7b, which inhibited VDR-mediated transcription (IC50  = 660 nM) without activating PPARδ-mediated transcription. However, inhibition of transcription mediated by other nuclear receptors was observed.