title: Synthesis and biological evaluation of a 3-positon epimer of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71).
abstract: 1alpha,25-Dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) (ED-71), an analog of active vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], possesses a hydroxypropoxy substituent at the 2beta-position of 1,25(OH)(2)D(3). 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-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)(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> or =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.
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
authors.forename: Susumi
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagashima
authors.forename: Naoko
authors.initials: N
authors.lastname: Imai
authors.forename: Keisuke
authors.initials: K
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Ishihara
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sugita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nihei
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Saito
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Takahashi
authors.forename: Noboru
authors.initials: N
authors.lastname: Kubodera
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D006801:Humans; D015394:Molecular Structure; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives
chemical_list: D014807:Vitamin D; D002117:Calcitriol; C547512:eldecalcitol