Synthesis of 2 alpha-Heteroarylalkyl Active Vitamin D-3 with Therapeutic Effect on Enhancing Bone Mineral Density in Vivo

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 al...

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Published inACS medicinal chemistry letters Vol. 4; no. 7; pp. 106 - 109
Main Authors Matsuo, Mild, Hasegawa, Asami, Takano, Masashi, Saito, Hiroshi, Kakuda, Shinji, Chida, Takayuld, Takagi, Ken-ichiro, Ochiai, Eiji, Horie, Kyohei, Harada, Yoshifumi, Takimoto-Kamimura, Midori, Takenouchi, Kazuya, Sawada, Daisuke, Kittaka, Atsushi
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 11.07.2013
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
bone mineral density
in vivo antiosteoporotic effect
DESIGN
Vitamin D
A-RING
osteocalcin
vitamin D receptor
D-3 ANALOGS
X-ray cocrystallographic analysis
EFFICIENT
NUCLEAR RECEPTOR
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml400098w