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

被引：30

作者：

Matsuo, Mild ^{[1
]}

Hasegawa, Asami ^{[1
]}

Takano, Masashi ^{[1
]}

Saito, Hiroshi ^{[2
]}

Kakuda, Shinji ^{[2
]}

Chida, Takayuld ^{[2
]}

Takagi, Ken-ichiro ^{[2
]}

Ochiai, Eiji ^{[2
]}

Horie, Kyohei ^{[2
]}

Harada, Yoshifumi ^{[2
]}

Takimoto-Kamimura, Midori ^{[2
]}

Takenouchi, Kazuya ^{[2
]}

Sawada, Daisuke ^{[1
]}

Kittaka, Atsushi ^{[1
]}

机构：

[1] Teikyo Univ, Fac Pharmaceut Sci, Itabashi Ku, Tokyo 1738605, Japan

[2] Teijin Pharma Ltd, Teijin Inst Biomed Res, Hino, Tokyo 1918512, Japan

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 07期

基金：

日本学术振兴会;

关键词：

Vitamin D; vitamin D receptor; X-ray cocrystallographic analysis; osteocalcin; bone mineral density; in vivo antiosteoporotic effect; NUCLEAR RECEPTOR; D-3; ANALOGS; A-RING; EFFICIENT; DESIGN;

D O I：

10.1021/ml400098w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

2 alpha-Heteroarylethyl-1 alpha,25-dihydroxyvitamin D-3 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 2 alpha-position, were synthesized. Among them, 2 alpha-[2-(tetrazol-2-yl)ethyl]-1 alpha,25-dihydroxyvitamin D-3 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 D-3. X-ray cocrystallographic analysis of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.

引用

页码：106 / 109

页数：4

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