Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators

J Clin Invest. 2006 Apr;116(4):892-904. doi: 10.1172/JCI25901. Epub 2006 Mar 9.

Abstract

Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine. In order to discover VDR ligands with less hypercalcemia liability, we sought to identify tissue-selective VDR modulators (VDRMs) that act as agonists in some cell types and lack activity in others. Here, we describe LY2108491 and LY2109866 as nonsecosteroidal VDRMs that function as potent agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but show poor activity in intestinal cells. Finally, these nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis.

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / metabolism
  • Acetates / pharmacology*
  • Animals
  • Arylsulfonates / chemical synthesis
  • Arylsulfonates / metabolism
  • Arylsulfonates / pharmacology*
  • Caco-2 Cells
  • Calcitriol / metabolism
  • Calcitriol / pharmacology
  • Cell Proliferation
  • Cells, Cultured
  • Colonic Neoplasms / metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Female
  • Humans
  • Hypercalcemia / metabolism
  • Intestines
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Ligands
  • Mice
  • Mice, Hairless
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Models, Biological
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Psoriasis / drug therapy
  • Rats
  • Receptors, Calcitriol / agonists
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction
  • Species Specificity
  • Thiophenes / chemical synthesis
  • Thiophenes / metabolism
  • Thiophenes / pharmacology*
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • Vitamin D / analogs & derivatives*
  • Vitamin D / chemical synthesis
  • Vitamin D / metabolism
  • Vitamin D / pharmacology*

Substances

  • Acetates
  • Arylsulfonates
  • LY 2108491
  • LY 2109866
  • Ligands
  • Receptors, Calcitriol
  • Thiophenes
  • dihydroxy-vitamin D3
  • Vitamin D
  • Calcitriol