2. Academic Validation
  3. Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists

Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists

  • Bioorg Med Chem Lett. 2015 Sep 15;25(18):3914-20. doi: 10.1016/j.bmcl.2015.07.047.
Yumi Matsui 1,  Takahiro Yamaguchi 2,  Takanori Yamazaki 2,  Masayuki Yoshida 2,  Masami Arai 2,  Naoki Terasaka 2,  Shoko Honzumi 2,  Kenji Wakabayashi 3,  Shinko Hayashi 2,  Daisuke Nakai 2,  Hiroyuki Hanzawa 3,  Kazuhiko Tamaki 4
Affiliations

Affiliations

  • 1 Daiichi Sankyo RD Novare Co., Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. Electronic address: matsui.yumi.gk@rdn.daiichisankyo.co.jp.
  • 2 R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Daiichi Sankyo RD Novare Co., Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 4 R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: tamaki.kazuhiko.s2@daiichisankyo.co.jp.
PMID: 26238323 DOI: 10.1016/j.bmcl.2015.07.047
Abstract

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys.

Keywords

Atherosclerosis; LXR agonists; Liver X receptors; Structure-based drug design; tert-Butyl benzoate.

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