Synthesis of 2α-Heteroarylalkyl Active Vitamin D3 with Therapeutic Effect on Enhancing Bone Mineral Density in Vivo

2α-Heteroarylethyl-1α,25-dihydroxyvitamin D3 analogues, which were designed to form a hydrogen bond between Arg274 of human vitamin D receptor (hVDR) and a nitrogen atom of the heteroaromatic ring at the 2α-position, were synthesized. Among them, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3...

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Published inACS medicinal chemistry letters Vol. 4; no. 7; pp. 671 - 674
Main Authors Matsuo, Miki, Hasegawa, Asami, Takano, Masashi, Saito, Hiroshi, Kakuda, Shinji, Chida, Takayuki, Takagi, Ken-ichiro, Ochiai, Eiji, Horie, Kyohei, Harada, Yoshifumi, Takimoto-Kamimura, Midori, Takenouchi, Kazuya, Sawada, Daisuke, Kittaka, Atsushi
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 11.07.2013
Subjects
Letter
bone mineral density
osteocalcin
in vivo antiosteoporotic effect
vitamin D receptor
Vitamin D
X-ray cocrystallographic analysis
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Summary:2α-Heteroarylethyl-1α,25-dihydroxyvitamin D3 analogues, which were designed to form a hydrogen bond between Arg274 of human vitamin D receptor (hVDR) and a nitrogen atom of the heteroaromatic ring at the 2α-position, were synthesized. Among them, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats, osteoporosis model animals, on enhancing bone mineral density than those of active vitamin D3. X-ray cocrystallographic analysis of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.
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ISSN:1948-5875
1948-5875
DOI:10.1021/ml400098w