Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor

Vitamin D receptor (VDR) ligands
are therapeutic agents that are
used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism
and have immense potential as therapeutic agents for autoimmune diseases,
cancers, and cardiovascular diseases. However, the major side effect
of VDR ligands, the development of hypercalcemia, limits their expanded
use. To develop tissue-selective VDR modulators, we have designed
vitamin D analogues with an adamantane ring at the side chain terminal,
which would interfere with helix 12, the activation function 2, and
modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin
D derivatives (ADTK1–4, 4b,a and 5a,b). These compounds showed high VDR affinities
(90% at maximum), partial agonistic activities (EC50 10–9–10–8 M with 40–80%
efficacy) in transactivation, and tissue-selective activity in target
gene expressions. We investigate the structure–activity relationships
of these compounds on the basis of their X-ray crystal structures.