Synthesis of 2α-heteroarylalkyl active vitamin D3 with therapeutic effect on enhancing bone mineral density in vivo

Miki Matsuo; Asami Hasegawa; Masashi Takano; Hiroshi Saito; Shinji Kakuda; Takayuki Chida; Ken Ichiro Takagi; Eiji Ochiai; Kyohei Horie; Yoshifumi Harada; Midori Takimoto-Kamimura; Kazuya Takenouchi; Daisuke Sawada; Atsushi Kittaka

doi:10.1021/ml400098w

Synthesis of 2α-heteroarylalkyl active vitamin D₃ with therapeutic effect on enhancing bone mineral density in vivo

Miki Matsuo, Asami Hasegawa, Masashi Takano, Hiroshi Saito, Shinji Kakuda, Takayuki Chida, Ken Ichiro Takagi, Eiji Ochiai, Kyohei Horie, Yoshifumi Harada, Midori Takimoto-Kamimura, Kazuya Takenouchi, Daisuke Sawada, Atsushi Kittaka

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

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 D ₃. X-ray cocrystallographic analysis of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.

Original language	English
Pages (from-to)	671-674
Number of pages	4
Journal	ACS Medicinal Chemistry Letters
Volume	4
Issue number	7
DOIs	https://doi.org/10.1021/ml400098w
Publication status	Published - Jul 11 2013
Externally published	Yes

Keywords

Vitamin D
X-ray cocrystallographic analysis
bone mineral density
in vivo antiosteoporotic effect
osteocalcin
vitamin D receptor

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1021/ml400098w

Cite this

Matsuo, M., Hasegawa, A., Takano, M., Saito, H., Kakuda, S., Chida, T., Takagi, K. I., Ochiai, E., Horie, K., Harada, Y., Takimoto-Kamimura, M., Takenouchi, K., Sawada, D., & Kittaka, A. (2013). Synthesis of 2α-heteroarylalkyl active vitamin D₃ with therapeutic effect on enhancing bone mineral density in vivo. ACS Medicinal Chemistry Letters, 4(7), 671-674. https://doi.org/10.1021/ml400098w

Matsuo, M, Hasegawa, A, Takano, M, Saito, H, Kakuda, S, Chida, T, Takagi, KI, Ochiai, E, Horie, K, Harada, Y, Takimoto-Kamimura, M, Takenouchi, K, Sawada, D & Kittaka, A 2013, 'Synthesis of 2α-heteroarylalkyl active vitamin D₃ with therapeutic effect on enhancing bone mineral density in vivo', ACS Medicinal Chemistry Letters, vol. 4, no. 7, pp. 671-674. https://doi.org/10.1021/ml400098w

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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 D 3. X-ray cocrystallographic analysis of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.",

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author = "Miki Matsuo and Asami Hasegawa and Masashi Takano and Hiroshi Saito and Shinji Kakuda and Takayuki Chida and Takagi, {Ken Ichiro} and Eiji Ochiai and Kyohei Horie and Yoshifumi Harada and Midori Takimoto-Kamimura and Kazuya Takenouchi and Daisuke Sawada and Atsushi Kittaka",

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AU - Matsuo, Miki

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AU - Takano, Masashi

AU - Saito, Hiroshi

AU - Kakuda, Shinji

AU - Chida, Takayuki

AU - Takagi, Ken Ichiro

AU - Ochiai, Eiji

AU - Horie, Kyohei

AU - Harada, Yoshifumi

AU - Takimoto-Kamimura, Midori

AU - Takenouchi, Kazuya

AU - Sawada, Daisuke

AU - Kittaka, Atsushi

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AB - 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 D 3. X-ray cocrystallographic analysis of the hVDR-ligand complex confirms that the new hydrogen bond formation stabilized the complex.

KW - Vitamin D

KW - X-ray cocrystallographic analysis

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KW - in vivo antiosteoporotic effect

KW - osteocalcin

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