Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs

…, H Jiang, JD Jacintho, MV Reddy, H Li…

Index: Boyer, Serge H.; Jiang, Hongjian; Jacintho, Jason D.; Reddy, Mali Venkat; Li, Haiqing; Li, Wenyu; Godwin, Jennifer L.; Schulz, William G.; Cable, Edward E.; Hou, Jinzhao; Wu, Rongrong; Fujitaki, James M.; Hecker, Scott J.; Erion, Mark D. Journal of Medicinal Chemistry, 2008 , vol. 51, # 22 p. 7075 - 7093

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Citation Number: 32

Abstract

Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TRβ1, K i< 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T3, PA 22c ...