TEI-9647とTEI-9648の構造活性相関研究 : 2α位と24位の化学修飾:最強のビタミンD受容体アンタゴニスト活性を目指して

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The unique structures and interesting biological profiles of the first vitamin D receptor (VDR) antagonists TEI-9647 and TEI-9648 prompted us to investigate the structure-activity relationships of these vitamin D_3 lactones and search for more potent anti-vitamin D molecules. Our general approach to develop vitamin D_3 lactones was, 1) to introduce the 2α-substitutions, that is, a methyl, 3-hydroxypropyl or 3-hydroxypropoxy group into TEI-9647 and TEI-9648 to improve their VDR binding affinity, 2) to also introduce a C24-substitution to stabilize the compound, 3) to determine the influence of the modified structures of the lactone moiety, on the stereochemistry, and on both VDR binding affinity and antagonistic activity, and 4) to investigate their biological effects after the C2α and C24-double modification of TEI-9647 and TEI-9648. In this review, we describe our striking results with C2α- and C24-functionalization of these VDR antagonists. The (23S,24S)-2α-(3-hydroxypropoxy)-24-propyl-TEI-9647 was found to have 851-fold improved antagonistic activity (IC_<50>=7.4pM) over the original TEI-9647 (IC_<50>=6.3nM).
2009-10-25