Synthesis of putative metabolites of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D(3) (ED-71).
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.
Ono
Yoshiyuki
Y
Chemistry Research Department I, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. onoysy@chugai-pharm.co.jp
Watanabe
Hiroyoshi
H
Taira
Ikuo
I
Takahashi
Keisuke
K
Ishihara
Jun
J
Hatakeyama
Susumi
S
Kubodera
Noboru
N
D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D010084:Oxidation-Reduction; D014807:Vitamin D / Q000031:analogs & derivatives
D050071:Bone Density Conservation Agents; D014807:Vitamin D; D002117:Calcitriol; C547512:eldecalcitol