2. Academic Validation
  3. Design and discovery of 2-oxochromene derivatives as liver X receptor β-selective agonists

Design and discovery of 2-oxochromene derivatives as liver X receptor β-selective agonists

  • Bioorg Med Chem Lett. 2015 Mar 15;25(6):1274-8. doi: 10.1016/j.bmcl.2015.01.047.
Takayuki Matsuda 1,  Ayumu Okuda 1,  Yuichiro Watanabe 1,  Tohru Miura 1,  Hidefumi Ozawa 1,  Ayako Tosaka 1,  Koichi Yamazaki 1,  Yuki Yamaguchi 1,  Sayaka Kurobuchi 1,  Minoru Koura 1,  Kimiyuki Shibuya 2
Affiliations

Affiliations

  • 1 Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
  • 2 Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan. Electronic address: k-sibuya@kowa.co.jp.
PMID: 25677664 DOI: 10.1016/j.bmcl.2015.01.047
Abstract

In an attempt to molecularly design liver X receptor (LXR) β-selective agonists, we discovered that the combination of the 2-oxochromene moiety (head) and the imidazoline-2,4-dione moiety (tail) plays an important role in the expression potency and selectivity toward LXRβ. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRβ-selective agonist that increased the HDL-C level without significantly elevating the TG level and resulted in a decreased lipid-accumulation area in the aortic arch in a high-fat-and-cholesterol-fed Bio F1B hamster. In this manuscript, we report the design, synthesis and pharmacology of these 2-oxochromene derivatives.

Keywords

2-Oxochromene; Anti-atherosclerosis; HDL-C; LXRβ-selective; Liver X receptor.

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