title: Synthesis of 2α-heteroarylalkyl active vitamin d3 with therapeutic effect on enhancing bone mineral density in vivo.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University , Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University , Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University , Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kakuda
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chida
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ochiai
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Horie
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Takimoto-Kamimura
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd. , Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University , Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawada
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University , Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
keywords: Vitamin D; X-ray cocrystallographic analysis; bone mineral density; in vivo antiosteoporotic effect; osteocalcin; vitamin D receptor