3L1B

Complex Structure of FXR Ligand-binding domain with a tetrahydroazepinoindole compound

3L1B の概要

• エントリーDOI: 10.2210/pdb3l1b/pdb
• 関連するPDBエントリー: 1OSH
• 分子名称: Farnesoid X receptor, 1-methylethyl 8-fluoro-1,1-dimethyl-3-{[4-(3-morpholin-4-ylpropoxy)phenyl]carbonyl}-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (3 entities in total)
• 機能のキーワード: nuclear receptor, fxr agonist, fxr ligand-binding domain, nucleus, receptor, transcription regulation, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27705.78

構造登録者

Xu, W.,Lundquist, J.T. (登録日: 2009-12-11, 公開日: 2010-03-02, 最終更新日: 2024-04-03)

主引用文献

Lundquist, J.T.,Harnish, D.C.,Kim, C.Y.,Mehlmann, J.F.,Unwalla, R.J.,Phipps, K.M.,Crawley, M.L.,Commons, T.,Green, D.M.,Xu, W.,Hum, W.T.,Eta, J.E.,Feingold, I.,Patel, V.,Evans, M.J.,Lai, K.,Borges-Marcucci, L.,Mahaney, P.E.,Wrobel, J.E.
Improvement of Physiochemical Properties of the Tetrahydroazepinoindole Series of Farnesoid X Receptor (FXR) Agonists: Beneficial Modulation of Lipids in Primates.
J.Med.Chem., 53:1774-1787, 2010

PubMed Abstract: In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.

PubMed: 20095622
DOI: 10.1021/jm901650u

実験手法

X-RAY DIFFRACTION (1.9 Å)