The vitamin D receptor is a nuclear hormone receptor that regulates cell proliferation, cell differentiation, calcium homeostasis and immunomodulation.  The receptor is activated by the vitamin D metabolite, 1,25-dihydroxyvitamin D3, which induces a cascade of events including the recruitment of coactivators that activate transcription of specific VDR target genes. Thousands of VDR agonists have been synthesized based on the secosteroid scaffold of 1,25-dihydroxyvitamin D3. However, most of these ligands are metabolically unstable, have sub-optimal drug-like properties, and induce hypercalcemia in vivo. The limited numbers of VDR antagonists reported bear the same secosteroid scaffold and thus exhibit the same problems encountered with VDR agonists. Herein, we report the development of non-secosteroidal antagonists for VDR with better drug-like properties in order to target VDR in vivo. This will aid in the development of new treatments for allergies, Crohn's disease, and sarcoidosis. Furthermore, we expect to develop a new therapy for patient suffering from hypercalcemia. The compounds presented here were derived from GW0742, a known compound identified as a VDR antagonist during a screening campaign with the NIH chemical and genomics center (NCGC) and is currently used as scaffold to develop highly selective modulator for VDR.

Development of selective non-secosteroidal vitamin D receptor inhibitors

248th National Meeting (2014)

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