Structural development of tetrachlorophthalimides as liver X receptor β (LXRβ)-selective agonists with improved aqueous solubility

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 4; pp. 796 - 801
• Main Authors: Nomura, Sayaka, Endo-Umeda, Kaori, Fujii, Shinya, Makishima, Makoto, Hashimoto, Yuichi, Ishikawa, Minoru
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.02.2018; Elsevier
• Subjects: Animals; ATP Binding Cassette Transporter 1 - genetics; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Humans; Hydrophobic and Hydrophilic Interactions; Life Sciences & Biomedicine; Liver X receptor; Liver X Receptors - agonists; LXR; Mice; Molecular Docking Simulation; Molecular Structure; Pharmacology & Pharmacy; Phthalimides - chemical synthesis; Phthalimides - chemistry; Phthalimides - pharmacology; Physical Sciences; RNA, Messenger - genetics; Science & Technology; Selective agonist; Solubility; Structure-Activity Relationship; THP-1 Cells; Water - chemistry; Liver X receptor; Selective agonist; LXR; ACTIVATION; LXR-BETA; METABOLISM; LIGANDS; ATHEROSCLEROSIS; ALPHA; MICE; IDENTIFICATION; EXPRESSION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.12.024

[Display omitted] LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. We have reported a series of tetrachlorophthalimide analogs as an LXRβ-selective agonist. However, they exhibited poor aqueous solubility probably due to its high hydrophobicity and highly rigid and plane structure. In this report, we present further structural development of tetrachloro(styrylphenyl)phthalimides as the LXRβ-selective agonists with improved aqueous solubility.