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 journalArticle

24 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 languageEnglish
Pages (from-to)671-674
Number of pages4
JournalACS Medicinal Chemistry Letters
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 11 2013
Externally publishedYes

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Calcitriol Receptors
Cholecalciferol
Therapeutic Uses
Bone Density
Minerals
Hydrogen
Hydrogen bonds
Bone
Calcitriol
Osteocalcin
X ray analysis
Osteosarcoma
Human Activities
Transcriptional Activation
Osteoporosis
Rats
Animals
Nitrogen
Animal Models
X-Rays

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

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

In: ACS Medicinal Chemistry Letters, Vol. 4, No. 7, 11.07.2013, p. 671-674.

Research output: Contribution to journalArticle

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
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. / Synthesis of 2α-heteroarylalkyl active vitamin D3 with therapeutic effect on enhancing bone mineral density in vivo. In: ACS Medicinal Chemistry Letters. 2013 ; Vol. 4, No. 7. pp. 671-674.
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