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

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 D 3 [1,25-(OH) 2 D 3 ] in an in vivo preclinical surrogate model of psoriasis.

Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia

“…We recently reported that vitamin D 3 derivatives with adamantane or lactone ring side chain substituents are cell type-selective VDR modulators (10). Ma et al (9) reported that nonsecosteroidal compounds act as noncalcemic and tissueselective VDR ligands. These compounds are potent VDR agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but are less potent in intestinal cells.…”

“…Combined dosing of 1,25(OH) 2 D 3 with other drugs is one approach to overcome its adverse effects (7,8). The development of synthetic vitamin D analogs that retain VDR transactivation but have low calcemic activity provides another approach (9). With an improved understanding of the mechanisms of VDR signaling, the possibility of identifying VDR ligands with selective action is emerging (10).…”

A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia

“…Additionally, we hypothesized that a synthetic compound could have other potential benefits to the elderly, such as improved neuromuscular function, anti-inflammatory/immunomodulation properties, inproved skin quality, and prevention of breast, colon, and prostate cancer. (13,(19)(20)(21)(22)(23)(24)(25)(26)(27) Therefore, compounds were evaluated for the ability to induce heterodimerization of VDR with RXR, resulting in the formation of a RXR-VDR heterodimer-ligand complex, which is a functional mediator of vitamin D action in cells. Alternatively, an RXR ligand will compete for RXR and disrupt RXR-VDR heterodimerization by driving the formation of the RXR-RXR homodimer.…”

“…The development of the stably transfected ROS17/2.8 cell line (RG-15) containing Ocn-Luc has been described. (26) Confluent RG-15 cells maintained in DMEM/F-12 medium (3:1) containing 5% FBS and 300 mg/mL of G418 at 378C were trypsinized (0.25% trypsin) and plated into white opaque 96-well cell culture plates (25,000 cells per well). After 24 hours, cells (in DMEM/F-12 medium containing 2% FBS) were treated with the indicated concentrations of the compounds.…”

“…Additionally, a vitamin D receptor ligand might have other potential benefits in the elderly, such as improved neuromuscular function and skin quality, anti-inflammatory/immunomodulation properties, and prevention of breast, colon, and prostate cancer. (13,(19)(20)(21)(22)(23)(24)(25)(26)(27) We describe in vitro and in vivo characteristics of VDRM2, which has a greater safety margin in terms of bone efficacy versus hypercalcemia than traditional secosteroidal vitamin D analogues.…”