Novel VDR antagonists based on the GW0742 scaffold

Bioorg Med Chem Lett. 2018 Feb 1;28(3):351-354. doi: 10.1016/j.bmcl.2017.12.041. Epub 2017 Dec 19.


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.

Keywords: Antagonist; Nuclear receptor; Peroxisome proliferation-activated receptor δ (PPARδ); Steroid receptor coactivator 2; Vitamin D receptor (VDR).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Receptors, Calcitriol / antagonists & inhibitors*
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics


  • Receptors, Calcitriol
  • Thiazoles
  • VDR protein, human
  • (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid