TY - JOUR
T1 - Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)-Selective Agonists
AU - Nomura, Sayaka
AU - Endo-Umeda, Kaori
AU - Makishima, Makoto
AU - Hashimoto, Yuichi
AU - Ishikawa, Minoru
N1 - Funding Information:
This work was supported in part by Grants-in Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology (Japan), and from the Japan Society for the Promotion of Science, and the Platform for Drug Discovery, Informatics, and Structural Life Science.
Publisher Copyright:
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2016/10/19
Y1 - 2016/10/19
N2 - Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP-binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP-1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand-binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ-selective agonist. Structural development led to (E)-4,5,6,7-tetrachloro-2-(2-styrylphenyl)isoindoline-1,3-dione (24 a), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP-1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists.
AB - Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP-binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP-1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand-binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ-selective agonist. Structural development led to (E)-4,5,6,7-tetrachloro-2-(2-styrylphenyl)isoindoline-1,3-dione (24 a), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP-1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists.
KW - ABCA1
KW - SREBP-1c
KW - agonists
KW - atherosclerosis
KW - liver X receptor (LXR)
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U2 - 10.1002/cmdc.201600305
DO - 10.1002/cmdc.201600305
M3 - Article
C2 - 27690261
AN - SCOPUS:84991608410
VL - 11
SP - 2347
EP - 2360
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 20
ER -