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.

维生素 D 受体是一种核激素受体，可调节细胞增殖、细胞分化和钙稳态。该受体被 1,25-二羟基维生素 D ₃内源性激活，其诱导受共激活因子结合调节的 VDR 靶基因的转录。VDR 拮抗剂和部分激动剂是基于维生素 D 的类固醇支架开发的。只有少数非类固醇 VDR 拮抗剂是已知的。在此，我们报告了使用 GW0742 作为支架的非类固醇 VDR 拮抗剂的合理设计。GW0742 是一种 PPARδ 激动剂，之前我们小组将其鉴定为 VDR 拮抗剂。包括用恶唑环替换噻唑环在内的若干修饰导致化合物7b抑制 VDR 介导的转录（IC₅₀  = 660 nM）而不激活 PPARδ 介导的转录。然而，观察到由其他核受体介导的转录抑制。