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

1 alpha,25-Dihydroxy-2 beta-(3-hydroxypropoxy)vitamin D-3 (ED-71), an analog of active vitamin D-3, 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], possesses a hydroxypropoxy substituent at the 2 beta-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)(2)D-3. Interestingly, during clinical development of ED-7 I, 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)(2)D-3, an epimer of 1,25(OH)(2)D-3 at the 3-position, shows equipotent and prolonged activity compared to 1,25(OH)(2)D-3 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 D-3 analogs were found to be 1,25(OH)(2)D-3 > ED-71 >= 3-epi-1,25(OH)(2)D-3 >> 3-epi-ED-71. ED-71 and 3-epi-ED-71 showed weak activity towards PTH suppression in our assays. (c) 2006 Elsevier Ltd. All rights reserved.