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

• Published in: Journal of medicinal chemistry Vol. 38; no. 4; pp. 695 - 707
• Main Authors: Yokoyama, Naokata, Walker, Gordon N, Main, Alan J, Stanton, James L, Morrissey, Michael M, Boehm, Charles, Engle, Allan, Neubert, Alan D, Wasvary, Jong M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.02.1995; Amer Chemical Soc
• Subjects: Acetates - chemistry; Acetates - pharmacology; Acetic Acid; Animals; Biological and medical sciences; Chemistry, Medicinal; General and cellular metabolism. Vitamins; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - chemistry; Hypolipidemic Agents - pharmacology; Life Sciences & Biomedicine; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Myocardial Contraction - drug effects; Oxamic Acid - analogs & derivatives; Oxamic Acid - chemistry; Oxamic Acid - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface - drug effects; Receptors, Cell Surface - metabolism; Receptors, Cytoplasmic and Nuclear - drug effects; Receptors, Cytoplasmic and Nuclear - metabolism; Science & Technology; Structure-Activity Relationship; Thyronines - chemistry; THYROID-HORMONE ANALOGS; RAT-LIVER; TRANSPORT; QUANTITATIVE STRUCTURE-ACTIVITY; THYROXINE ANALOGS; THYROMIMETIC ACTIVITIES; EXPERIMENTAL HYPOTHYROIDISM; BINDING-SITES; PLASMA-MEMBRANE; TRIIODOTHYRONINE T3; Rat; Rodentia; Oral administration; In vitro; Cholesterol; In vivo; Vertebrata; Mammalia; Structure activity relation; Animal; Phenols; Carboxamide; Dicarboxylic acid; Triiodothyronine; Fluorine Organic compounds; Chemical synthesis; Antilipemic agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00004a015

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-T-3) were prepared and tested in vitro for binding to the rat liver nuclear L-T-3 receptor and the rat membrane L-T-3 receptor. The structure-activity relationships for these compounds are described, with 7f, 23a, 29c, 33a, 37b, and 41 showing excellent potency (IC(50)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 mu M). 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 ED(50)'s of 20 and 5 mu g/kg po, respectively, and a lack of cardiac side effects in rats at doses as high as 10 and 25 mg/kg po, respectively.