Structural development of non-secosteroidal vitamin D receptor (VDR) ligands without any asymmetric carbon

Bioorg Med Chem. 2018 Dec 15;26(23-24):6146-6152. doi: 10.1016/j.bmc.2018.11.008.

Takashi Misawa ¹, Genichiro Tsuji ², Takeo Takahashi ², Eiji Ochiai ³, Ken-Ichiro Takagi ³, Kyohei Horie ³, Shinji Kakuda ³, Midori Takimoto-Kamimura ³, Masaaki Kurihara ⁴, Yosuke Demizu ⁵

Affiliations

1 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan. Electronic address: misawa@nihs.go.jp.
2 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan.
3 Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., Tokyo 191-8512, Japan.
4 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan; Department of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara City, Tochigi 324-8501, Japan. Electronic address: mkurihara@iuhw.ac.jp.
5 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan. Electronic address: demizu@nihs.go.jp.

PMID: 30446437 DOI: 10.1016/j.bmc.2018.11.008

Abstract

Non-secosteroidal VDR ligands without any assymmetric carbon were designed and synthesized based on the structure of the previously reported non-secosteroidal VDR agonist LG190178. The VDR-agonistic activity of all synthesized compounds was evaluated, and 7b emerged as a potent agonist activity with an EC₅₀ value of 9.26 nM. Moreover, a docking simulation analysis was also performed to determine the binding mode of 7b with VDR-LBD.

Keywords

Asymmetric carbon; Docking study; Non-secosteroid; Vitamin D receptor.

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