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Novel VDR antagonists based on the GW0742 scaffold
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2017-12-19 , DOI: 10.1016/j.bmcl.2017.12.041
Kelly A Teske 1 , Jonathan W Bogart 1 , Leggy A Arnold 1
Affiliation  

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.



中文翻译:

基于 GW0742 支架的新型 VDR 拮抗剂

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。

更新日期:2017-12-19
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