Ono Yoshiyuki, Watanabe Hiroyoshi, Taira Ikuo, Takahashi Keisuke, Ishihara Jun, Hatakeyama Susumi, Kubodera Noboru
Chemistry Research Department I, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Steroids. 2006 Jul;71(7):529-40. doi: 10.1016/j.steroids.2005.11.001. Epub 2006 Apr 25.
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)] is under phase III clinical trials in Japan for the treatment of osteoporosis and bone fracture prevention. Since ED-71 has a substituent at the 2beta-position of the A-ring, it is recognized that the metabolic pathway of ED-71 might be more complicated than 1,25(OH)(2)D(3) because of metabolism at the 2beta-position substituent in addition to the inherent metabolism of the side chain. To clarify the metabolism of hydroxypropoxy substituent of the 2beta-positon and a combination of metabolism between side chain and 2beta-positon, four putative metabolites of ED-71 have been prepared as authentic samples. The metabolites at the 2beta-positon, the methyl ester derivative considered as an ester standard of the oxidized metabolite and the tetraol derivative as the truncated metabolite were synthesized from alpha-epoxide, a key intermediate of ED-71 synthesis. The combination metabolites between side chain and 2beta-positon, the 24(S)- and 24(R)-pentaols were synthesized using Trost's convergent method.
1α,25-二羟基-2β-(3-羟基丙氧基)维生素D(3)（ED-71）是活性维生素D(3)即1α,25-二羟基维生素D(3) [1,25(OH)₂D₃]的类似物，目前正在日本进行治疗骨质疏松症和预防骨折的III期临床试验。由于ED-71在A环的2β位有一个取代基，人们认为ED-71的代谢途径可能比1,25(OH)₂D₃更复杂，因为除了侧链固有的代谢外，2β位取代基也会发生代谢。为了阐明2β位羟基丙氧基取代基的代谢以及侧链与2β位之间的代谢组合，已制备了四种推定的ED-71代谢物作为对照品。2β位的代谢物、被视为氧化代谢物酯标准品的甲酯衍生物和作为截短代谢物的四醇衍生物是由α-环氧化物合成的，α-环氧化物是ED-71合成的关键中间体。使用特罗斯特汇聚法合成了侧链与2β位之间的组合代谢物24(S)-和24(R)-戊醇。
