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91.
Vitamin D receptor (VDR) antagonists have attracted significant levels of interest because of their 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, TEI-9647 and TEI-9648 (25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone), with the goal of 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 the field of VDR agonists would help us identify potent antagonists. First 2alpha-modified TEI-9647 analogues were synthesized, and then 24-substitution to stabilize the lactone structure under physiological conditions was investigated. Finally, 2alpha-modified 24-methyl-, 24,24-dimethyl-, and 24,24-ethano-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone analogues were synthesized. The synthesis of the 24,24-ethano-TEI lactone was accomplished through Ru-catalyzed intermolecular enyne metathesis of the alkynone CD-ring side chain with ethylene to give a dienone, followed by regioselective cyclopropanation. It was found that 2alpha,24,24-trimethyl-TEI-9647 (39) possessed an antagonistic activity (IC(50)=0.093 nM) approximately 90 times that of the original TEI-9647 (IC(50)=8.3 nM). 相似文献
92.
Sho Imai Kenichi Watanabe Astushi Yamazaki Sachiko Yoshihashi Akira Uritani Seiji Tasaki Setsuo Satoh 《辐射防护》2020,40(6):540-544
We fabricated the spheroid neutron diffractometer with 79 neutron detector rings using the transparent rubber sheet type Eu: LiCaAlF6 scintillators and wavelength-shifting fibers.We confirmed that the fabricated detector shows a clear neutron peak and can discriminate neutron and gamma-ray events in a signal pulse spectrum.We additionally checked that the fabricated diffractometer can detect a neutron diffraction peak of ferrite powder at Kyoto University Accelerator-driven Neutron So... 相似文献