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Novel VDR antagonists based on the GW0742 scaffold.

ABSTRACT: 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 PPAR? 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 PPAR?-mediated transcription. However, inhibition of transcription mediated by other nuclear receptors was observed.

SUBMITTER: Teske KA

PROVIDER: S-EPMC6008168 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Novel VDR antagonists based on the GW0742 scaffold.

Teske Kelly A KA Bogart Jonathan W JW Arnold Leggy A LA

Bioorganic & medicinal chemistry letters 20171219 3

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 D<sub>3</sub>, 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- ...[more]

PMID: 29287957

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