Synthesis and Structure-Activity Relationships of Oxamic Acid and Acetic Acid Derivatives Related to L-Thyronine

Abstract

Aryloxamic acids 7 and 23, (arylamino)acetic acids 29, arylpropionic acids 33, arylthioacetic acids 37, and (aryloxy)acetic acid 41 related to L-triiodothyronine (L-T3) were prepared and tested in vitro for binding to the rat liver nuclear L-T3 receptor and the rat membrane L-T3 receptor. The structure-activity relationships for these compounds are described, with 7f, 23a, 29c, 33a, 37b, and 41 showing excellent potency (IC50's of 0.19, 0.16, 1.1, 0.11, 3.5, and 0.10 nM, respectively) to the nuclear receptor and significantly lower binding affinity to the membrane receptor (IC50's > 5 microM). Some of these compounds, especially in the oxamic acid series 7 and 23, showed an unprecedented potency for methyl-substituted derivatives such as 7f and 23a. Compounds 7f and 23a showed good lipid lowering effects in rats with ED50's of 20 and 5 micrograms/kg po, respectively, and a lack of cardiac side effects in rats at doses as high as 10 and 25 mg/kg po, respectively.

Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index

“…Both activities are evident from the clinical profiles of patients with hyper-and hypothyroidism (7)(8)(9) and from studies in TR knockout mice (10). Unfortunately, despite efforts spanning nearly 40 years, neither activity could be achieved by using THs or related analogs without eliciting significant adverse effects on cardiac function and the thyroid hormone axis (THA) (11,12).…”

Thyroid Hormones and Thyromimetics

“…As axitirome exhibited a 100-fold preference for binding to nuclei of HepG2 cells over cardiac myocytes [251], selective tissue uptake was proposed to explain the compound's selectivity, as similarly demonstrated for the first-generation selective thyromimetics such as SKF-94901. In preclinical animal models, axitirome demonstrated potent cholesterollowering activity free of L-T 3 -like cardiovascular and thermogenic effects [255].…”

“…Axitirome (CGS-26214, 9) and CGS-23425 (10) were the most important members of this new extensively studied class of thyromimetics [251][252][253][254]. Notably, both axitirome and CGS-23425 had methyl substituents at the R 3 -and R 5 -positions, and axitirome also featured a large hydrophobic group at the R 0 3 -position (a-OH-p-F-benzyl group) (Fig.…”

Design, synthesis, and biological evaluation of bifunctional thyrointegrin inhibitors: new anti-angiogenesis analogs

“…The bis-aryliodonium triflate (14) was prepared from compound (13) according to the aryliodonium formation method described by Yokoyama et al 62 . Compound (13) was prepared on both small and high scales by the refluxing methyletherification procedure of 2-isopropylphenol (12) using cesium carbonate as a proton trap.…”