1. Academic Validation
  2. Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and β-selectivity of liver X receptor agonist

Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and β-selectivity of liver X receptor agonist

  • Bioorg Med Chem. 2016 Aug 15;24(16):3436-46. doi: 10.1016/j.bmc.2016.05.048.
Minoru Koura 1 Yuki Yamaguchi 1 Sayaka Kurobuchi 1 Hisashi Sumida 1 Yuichiro Watanabe 1 Takashi Enomoto 1 Takayuki Matsuda 1 Ayumu Okuda 1 Tomoaki Koshizawa 1 Yuki Matsumoto 1 Kimiyuki Shibuya 2
Affiliations

Affiliations

  • 1 Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
  • 2 Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan. Electronic address: k-sibuya@kowa.co.jp.
Abstract

Our research found that the 2-hydroxyacetophenone derivative is an outstanding linker between the 1,1-bistrifluoromethylcarbinol moiety and the imidazolidine-2,4-dione moiety to enhance the potency and β-selectivity of liver X receptor (LXR) agonist in our head-to-tail molecular design. The incorporation of this linker is 20-fold more potent than our previous compound (2) for LXR β agonistic activity (EC50) in a GAL-4 luciferase assay. Furthermore, we also identified 5-[5-(1-methylethoxy)pyridyl-2-yl]-5-methylimidazoline-2,4-dione (54), which lowers the lipophilicity of 2-hydroxyacetophenone derivative. We revealed that a combination of our newly developed linker and hydantoin (54) plays a pivotal role in improving the potency and selectivity of LXRβ. The optically separated (-)-56 increases high-density lipoprotein Cholesterol levels without elevating plasma triglyceride levels and results in a decrease of the lipid accumulation area in the aortic arch in a high-fat- and cholesterol-fed low-density lipoprotein receptor knock-out mice. In this manuscript, we report that (-)-56 is a highly potent and β-selective LXR Agonist for use in the treatment of atherosclerosis.

Keywords

2-Hydroxyacetophenone; ABCA1; Anti-atherosclerosis; HDL-C; Liver X receptor (LXR) β-selective.

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