Design and Synthesis of Highly Potent Vitamin D Receptor Antagonists based on the Structural Development of Vitamin D3-26, 23-lactone

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  • ビタミンＤ３‐２６，２３‐ラクトンを基盤とするビタミンＤ受容体アンタゴニストの設計と合成
  • ビタミン D3 26 23 ラクトン オ キバン ト スル ビタミン D ジュヨウタイ アンタゴニスト ノ セッケイ ト ゴウセイ

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Vitamin D receptor (VDR) 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 D3 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-1α-hydroxyvitamin D3-26, 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, 2α-modified TEI analogs were synthesized to improve VDR binding affinity, and then, 24-substitution was next investigated to enhance lactone stability under physiological conditions. Finally, 2α-modified 24-alkyl-, 24, 24-dimethyl-, and 24, 24-ethano-25-dehydro-1α-hydroxyvitamin D3-26, 23-lactones were synthesized. It was found that (23S, 24S) -2α- (3-hydroxypropoxy) -24-propyl-TEI-9647 was found to possess almost 1000-fold improved antagonistic activity (IC50=7.4 pM) over the original TEI-9647 (IC50= 6.3 nM).

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