Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and β-selectivity of liver X receptor agonist.
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.
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Minoru
M
Koura
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Yuki
Y
Yamaguchi
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Sayaka
S
Kurobuchi
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Hisashi
H
Sumida
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Yuichiro
Y
Watanabe
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Takashi
T
Enomoto
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Takayuki
T
Matsuda
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Ayumu
A
Okuda
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Tomoaki
T
Koshizawa
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan.
Yuki
Y
Matsumoto
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.
Kimiyuki
K
Shibuya
D000098:Acetophenones / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D059305:Diet, High-Fat; D000071518:Liver X Receptors / Q000819:agonists*; D051379:Mice; D018345:Mice, Knockout; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
D000098:Acetophenones; D000071518:Liver X Receptors; C038699:acetophenone
2-Hydroxyacetophenone; ABCA1; Anti-atherosclerosis; HDL-C; Liver X receptor (LXR) β-selective