Synthesis and biological evaluation of a 3-positon epimer of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)

• Published in: Journal of steroid biochemistry and molecular biology 2007-03, Vol.103 (3-5), p.222-226
• Main Authors: Hatakeyama, Susumi, Nagashima, Satoshi, Imai, Naoko, Takahashi, Keisuke, Ishihara, Jun, Sugita, Atsuko, Nihei, Takeshi, Saito, Hitoshi, Takahashi, Fumiaki, Kubodera, Noboru
• Format: Article
• Language: English
• Subjects: 1α,25-Dihydroxy-2β-(3-hydroxypropoxy)vitamin D3; 1α,25-Dihydroxyvitamin D3; 3-Epi-ED-71; Active vitamin D3; Biological and medical sciences; ED-71; General pharmacology; Medical sciences; Parathyroid hormone; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2006.12.025

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)2D3 at the 3-position, shows equipotent and prolonged activity compared to 1,25(OH)2D3 at 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 D3 analogs 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.