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Structure-activity relationship studies on vitamin D-based selective SREBP/SCAP inhibitor KK-052
Fumihiro Kawagoe1, Sayuri Mototani1, Aileen Mendoza2
1Faculty of Pharmaceutical Sciences, Teikyo University Itabashi-ku Tokyo 173-8605 Japan akittaka@pharm.teikyo-u.ac.jp.
Abstract:
Vitamin D3 metabolites block lipid biosynthesis by promoting degradation of the complex of sterol regulatory element-binding protein (SREBP) and SREBP cleavage-activating protein (SCAP) independent of their effects on the vitamin D receptor (VDR). We previously reported the development of KK-052, the first vitamin D-based SREBP inhibitor that mitigates hepatic lipid accumulation without VDR-mediated calcemic action in mice. Herein we extend our previous work to synthesize KK-052 analogues. Various substituents were introduced to the phenyl ring of KK-052, and two KK-052 analogues were found to exhibit more potent SREBP/SCAP inhibitory activity than KK-052, whereas they all lack VDR activity. These new KK-052 analogues may be suited for further development as VDR-silent SREBP/SCAP inhibitors.
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