Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and Their Prodrugs

• DOI: 10.1021/jm800824d
• Publication Date: 2008-11-01T06:00:31Z
• Authors: Serge H. Boyer; Hongjian Jiang; Jason D. Jacintho; Mali Venkat Reddy; Haiqing Li; Wenyu Li; Jennifer L. Godwin; William G. Schulz; Edward E. Cable; Jinzhao Hou; Rongrong Wu; James M. Fujitaki; Scott J. Hecker; Mark D. Erion
• Keywords: Thyroid hormone receptor

Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs extrahepatic tissues and thereby improve therapeutic index. Nine PAs showed excellent TR binding affinities (TRβ1, Ki < 10 nM), most them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike corresponding carboxylic analogue T3, PA 22c liver-selective by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity liver while having no effect heart. Because low oral bioavailability 22c, series prodrugs was screened for efficacy CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) potent lipid (ED50 0.4 mg/kg, po) good (40%, rat) selected development treatment hypercholesterolemia.