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

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.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…For example, compound 41 was prepared as a prodrug for a thyroid hormone receptor agonist, and was shown to lower cholesterol and triglyceride levels with decreased impact on other tissues [83,84]. A variety of compounds in this vein has been prepared, and the various stereoisomers were separable by column chromatography and HPLC on a nonracemic column.…”

Picolinamides as Effective Ligands for Copper‐Catalysed Aryl Ether Formation: Structure–Activity Relationships, Substrate Scope and Mechanistic Investigations

“…[44] Aryl ethers bearing carbonaceous side chains in the ortho position have also shown biological activity, for example triclosan derivatives showing antimalarial effects [62,63] and thyroid receptor antagonists derived from thyroxin. [64] Other examples can be found of various medicinal applications of substituted aryl ethers. [41][42][43] The formation of such hindered aryl ethers in Ullmann chemistry is rare, especially in intermolecular reactions, and only a few examples have been reported.…”

Thyroid Hormones and Thyromimetics

“…P450-Activated Prodrug MB07811 After investigating the biological properties of ligands displaying poor bioavailability, containing an R 1 -phosphonic acid side chain, Metabasis developed the liver-activated prodrug MB07811 (21, Fig. 17) [283]. Pharmacokinetic studies in rats demonstrated that MB07811 undergoes first-pass hepatic extraction and subsequent cleavage by cytochrome P450, which generates the free methylphosphonic acid MB07344 (22, Fig.…”