Synthesis and biological evaluation of a 3-positon epimer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)
Synthesis and biological evaluation of a 3-positon epimer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)
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DOI：
10.1016/j.jsbmb.2006.12.025
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发表时间：
2007-03
期刊：
影响因子：
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通讯作者：
S. Hatakeyama;S. Nagashima;N. Imai;Keisuke Takahashi;Jun Ishihara;A. Sugita;T. Nihei;H. Saito;F. Takahashi;N. Kubodera
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作者：
S. Hatakeyama;S. Nagashima;N. Imai;Keisuke Takahashi;Jun Ishihara;A. Sugita;T. Nihei;H. Saito;F. Takahashi;N. Kubodera
1α,25-二羟基-2β-(3-羟基丙氧基)维生素 D3(ED-71) 是活性维生素 D3 的类似物，1α,25-二羟基维生素 D3[1,25(OH)2D3]，在 1,25(OH)2D3 的 2β 位上具有羟基丙氧基取代基。 ED-71 对骨骼具有有效的生物学作用，目前正在进行预防骨折的 III 期临床研究。众所周知，甲状旁腺激素（PTH）的合成和分泌受1,25(OH)2D3的调节。有趣的是，在 ED-71 的临床开发过程中，骨质疏松患者的血清完整 PTH 在接受 ED-71 治疗后没有显着变化。然而，原因尚不清楚。布朗等人。据报道，3-epi-1,25(OH)2D3（3 位 1,25(OH)2D3 的差向异构体）与 1,25(OH)2D3at 相比，在抑制 PTH 分泌方面表现出等效且持久的活性。由于 ED-71 在 2 位有一个庞大的羟基丙氧基取代基，因此可能会阻止相邻且空间位阻的 3 位的差向异构化，这可能是临床研究中观察到的其 PTH 抑制效力较弱的原因。我们对 ED-71 在 3 位的差向异构化以及 3-epi-ED-71 抑制 PTH 分泌的生物效力非常感兴趣。在本研究中，描述了 3-epi-ED-71 的合成以及使用牛甲状旁腺细胞体外抑制 PTH 的研究。维生素D3类似物的抑制效力为1,25(OH)2D3>ED-71≥3-epi-1,25(OH)2D3≫3-epi-ED-71。在我们的测定中，ED-71 和 3-epi-ED-71 对 PTH 抑制表现出较弱的活性。
1α,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D3(ED-71), an analog of active vitamin D3, 1α,25-dihydroxyvitamin D3[1,25(OH)2D3], possesses a hydroxypropoxy substituent at the 2β-position of 1,25(OH)2D3. ED-71 has potent biological effects on bone and is currently under phase III clinical studies for bone fracture prevention. It is well-known that the synthesis and secretion of parathyroid hormone (PTH) is regulated by 1,25(OH)2D3. Interestingly, during clinical development of ED-71, serum intact PTH in osteoporotic patients did not change significantly upon treatment with ED-71. The reason remains unclear, however. Brown et al. reported that 3-epi-1,25(OH)2D3, an epimer of 1,25(OH)2D3at the 3-position, shows equipotent and prolonged activity compared to 1,25(OH)2D3at suppressing PTH secretion. Since ED-71 has a bulky hydroxypropoxy substituent at the 2-position, epimerization at the adjacent and sterically hindered 3-position might be prevented, which may account for its weak potency in PTH suppression observed in clinical studies. We have significant interest in ED-71 epimerization at the 3-position and the biological potency of 3-epi-ED-71 in suppressing PTH secretion. In the present studies, synthesis of 3-epi-ED-71 and investigations of in vitro suppression of PTH using bovine parathyroid cells are described. The inhibitory potency of vitamin D3analogs were found to be 1,25(OH)2D3>ED-71≥3-epi-1,25(OH)2D3≫3-epi-ED-71. ED-71 and 3-epi-ED-71 showed weak activity towards PTH suppression in our assays.