Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and Their Prodrugs
Authors
Boyer, Serge H.Jiang, Hongjian
Jacintho, Jason D.
Reddy, Mali Venkat
Li, Haiqing
Li, Wenyu
Godwin, Jennifer L.
Schulz, William G.
Cable, Edward Earl
Hou, Jinzhao
Wu, Rongrong
Fujitaki, James M.
Hecker, Scott J.
Erion, Mark D.
UMass Chan Affiliations
Graduate School of Biomedical SciencesDocument Type
Journal ArticlePublication Date
2008-11-04
Metadata
Show full item recordAbstract
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 (TRbeta 1, 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 T 3, PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED 50 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.Source
J Med Chem. 2008 Nov 1. Link to article on publisher's siteDOI
10.1021/jm800824dPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32811PubMed ID
18975928Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/jm800824d