GSBS Student Publications

Title

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

Publication Date

2008-11-04

UMMS Affiliation

Graduate School of Biomedical Sciences; boyer@mbasis.com.

Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences

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 (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.

DOI of Published Version

10.1021/jm800824d

Source

J Med Chem. 2008 Nov 1. Link to article on publisher's site

Journal/Book/Conference Title

Journal of medicinal chemistry

Related Resources

Link to Article in PubMed

PubMed ID

18975928

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