コムロ アキヒコ   KOMURO AKIHIKO
  小室 晃彦
   所属   新潟薬科大学  薬学部 薬学科
   職種   教授
言語種別 英語
発行・発表の年月 2019/06
形態種別 論文
査読 査読有り
標題 Structural requirements of cholenamide derivatives as the LXR ligands.
執筆形態 共著
掲載誌名 Bioorganic & medicinal chemistry letters
掲載区分国外
巻・号・頁 29(11),pp.1330-1335
著者・共著者 Saida-Tamiya Kana, Tamiya Minoru, Sekiya Genki, Isobe Kazunori, Kitazawa Takaaki, Isaka Nobuhisa, Matsukawa Ayako, Kawahara Kohichi, Komuro Akihiko, Ishiguro Masaji
概要 A study of the structural requirements of cholic acid derivatives as liver X receptor (LXR) ligands was performed. A model of cholenamide derivative 1 complexed with LXR showed that the C24 carbonyl oxygen forms a hydrogen bond with His435 located close to Trp457. The N,N-dimethyl group is located in a hydrophobic pocket. Based on these data, we designed compounds with high affinity for LXRs. Cholenamide derivatives 1-11 were synthesized from 3β-acetyl-Δ5-cholenic acid 20, and lactams 12-19 were synthesized from alcohol 25. Tertiary amides 3 and 4 showed higher activity in reporter assays, and compounds with hydrophobic residues exhibited the highest activity of all derivatives. The stereochemistry at C23 was found to be an important determinant of EC50 and gene transactivation, as each isomer exhibited different activity.
DOI 10.1016/j.bmcl.2019.03.051
ISSN 1464-3405
PMID 30952591