[Creation of highly potent vitamin D receptor antagonists]

Vitamin D receptor antagonist has attracted significant level of interests because of its potential utility in the treatment of Paget's disease, which is known as the most flagrant example of disordered bone remodeling and the second most common bone disease after osteoporosis in Anglo-Saxons. Recent studies on Paget's disease suggested a specific increase in osteoclasts sensitivity to the differentiation activity of active vitamin D(3) as the principal mechanism for abnormal bone formation. We set out to conduct a structure-activity relationship study on the first VDR antagonists of TEI-9647 and TEI-9648 (25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone) toward improved VDR antagonistic activity. Given that both potent agonists and antagonists must have high affinity for the VDR, we hoped that our accumulated knowledge in VDR agonists would help us identify potent antagonists. First, 2alpha-modified TEI-9647 analogs were synthesized, and then, 24-substitution was next investigated to stabilize its lactone structure under the physiological conditions. Finally, 2alpha-modified 24-methyl-, 24,24-dimethyl-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone analogs were synthesized. It was found that 2alpha,24,24-trimethyl-TEI-9647 was found to possess approximately 90-fold improved antagonistic activity (IC(50) 0.093 nM) over the original TEI-9647 (IC(50) 8.3 nM).