title: Design and discovery of 2-oxochromene derivatives as liver X receptor β-selective agonists.
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.
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Takayuki
authors: T
authors: Matsuda
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Ayumu
authors: A
authors: Okuda
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Yuichiro
authors: Y
authors: Watanabe
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Tohru
authors: T
authors: Miura
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Hidefumi
authors: H
authors: Ozawa
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Ayako
authors: A
authors: Tosaka
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Koichi
authors: K
authors: Yamazaki
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Yuki
authors: Y
authors: Yamaguchi
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Sayaka
authors: S
authors: Kurobuchi
authors: Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayam, Tokyo 189-0022, Japan.
authors: Minoru
authors: M
authors: Koura
authors: 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.
authors: Kimiyuki
authors: K
authors: Shibuya
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000097:blood; D003374:Coumarins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D059305:Diet, High-Fat; D015195:Drug Design; D006827:Hydantoins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D048288:Imidazolines / Q000737:chemistry; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: C000603772:5-(4-methoxyphenyl)-5-methyl-3-(4-((2-oxo-8-n-propyl-4-(trifluoromethyl)-2H-chromen-7-yl)oxy)butyl)imidazolidine-2,4-dione; D001578:Benzopyrans; D008076:Cholesterol, HDL; D003374:Coumarins; D006827:Hydantoins; D048288:Imidazolines; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors
keywords: 2-Oxochromene; Anti-atherosclerosis; HDL-C; LXRβ-selective; Liver X receptor