Design and Synthesis of Vitamin D Receptor Antagonists : Remedy for Pagets Desease

最近，具有维生素D受体（VDR）拮抗活性的化合物因其治疗Paget病的可能性而受到了相当大的关注，Paget病是盎格鲁-撒克逊人仅次于骨质疏松症的第二大常见骨病。已知1α-羟基维生素d_3 -26,23-内酯（TEI-9647）具有抗VDR活性（IC_<50> 8.3 nM），但该化合物对VDR的亲和力较低，在血液中不稳定。我们研究了通过修饰TEI-9647的C2α和C24位点来提高TEI-9647对VDR的亲和力和血液稳定性。在本项目中，我们利用低价cr介导的烯丙化，开发了24,24-二甲基化TEI-9647的新的cd环内酯部分和24,24-乙醇的螺旋结构TEI-9647，利用ru催化的炔酮和乙烯之间的分子间酶转化得到二烯酮，然后进行区域选择性环丙烷化。基于x射线晶体学分析，确定了24,24-二甲基和24,24-乙醇内酯新侧链C23位置的立体化学。结果表明，合成的24,24-二甲基化TEI-9647的抗d活性比首次报道的vdr拮抗剂TEI-9647的抗d活性高12倍以上。对C2α和C24进行甲基双修饰，其拮抗活性（IC_<50> 0.093 nM）是TEI-9647的89倍。据我们所知，TEI-9647的2α，24,24-三甲基类似物是迄今为止最有效的vdr拮抗剂。TEI-9647的2α-甲基-24,24-乙醇类似物的抗d活性比TEI-9647高19倍以上。我们相信这些具有强效抗d活性的类似物将有助于理解VDR上拮抗活性表达的机制，并为治疗佩吉特病的患者找到新药的种子。

Recently, compounds with vitamin D receptor (VDR) antagonistic activity have received considerable attention because of their possibility to treat for Paget's disease, which is the second most common bone disease after osteoporosis in Anglo-Saxons. It is known that 1α-hydroxyvitamin D_3-26,23-lactone (TEI-9647) shows VDR antagonistic activity (IC_<50> 8.3 nM), while this compound has low affinity for the VDR and instability in blood. We investigated to enhance the affinity for the VDR and stability in blood by modifying C2α and C24 positions of TEI-9647. In this project, we have developed the short step synthesis of the new CD-ring lactone parts of 24,24-dimethylated TEI-9647 using low-valent Cr-mediated allylation and 24,24-ethano TEI-9647 with a spiro-structure using Ru-catalyzed intermolecular enyne metathesis between alkynone and ethylene to give dienone followed by regioselective cyclopropanation. Stereochemistry at the C23 position on the new side chains of 24,24-dimethyl and 24,24-ethano lactone was determined based on their X-ray crystallographic analyses.It was found that the synthesized 24,24-dimethylated TEI-9647 showed more than 12 fold higher anti-D activity than that of the first reported VDR-antagonist TEI-9647. Moreover, double modification at both C2α and C24 with methyl groups showed 89 times more potent antagonistic activity (IC_<50> 0.093 nM) than that of TEI-9647. As far as we know, this 2α,24,24-trimethyl analog of TEI-9647 is the most potent VDR-antagonist so far. 2α-Methyl-24,24-ethano analog of TEI-9647 showed more than 19 fold higher anti-D activity than that of TEI-9647.We believe these analogs with potent anti-D activity would contribute to understanding the mechanisms involved in the expression of antagonistic activity on the VDR as well as to finding the seeds of new medicines for treating patients of Paget's disease.